Apparatus for effective ablation and nerve sensing associated with denervation

ABSTRACT

An intravascular catheter for nerve activity ablation and/or sensing includes one or more needles advanced through supported guide tubes (needle guiding elements) which expand to contact the interior surface of the wall of the renal artery or other vessel of a human body allowing the needles to be advanced though the vessel wall into the extra-luminal tissue including the media, adventitia and periadvential space. The catheter also includes structures which provide radial and lateral support to the guide tubes so that the guide tubes open uniformly and maintain their position against the interior surface of the vessel wall as the sharpened needles are advanced to penetrate into the vessel wall. Electrodes near the distal ends of the needles allow sensing of nerve activity before and after attempted renal denervation. In a combination embodiment ablative energy or fluid is delivered from the needles in or near the adventitia to ablate nerves outside of the media while sparing nerves within the media.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 14/963,179 filed on Dec. 8, 2015, which in turn isa continuation-in-part of U.S. patent application Ser. No. 14/063,907entitled “Intravascular Catheter with Peri-vascular Nerve ActivitySensors,” filed on Oct. 25, 2013, the disclosures of each of theforegoing applications of which are incorporated in their entiretiesherein by reference.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claimis identified in the Application Data Sheet as filed with the presentapplication are hereby incorporated by reference under 37 CFR 1.57.

BACKGROUND Field of the Invention

This invention relates in some aspects to the field of devices thatmonitor, stimulate, and/or ablate tissue and nerve fibers primarily inthe adventitial and/or periadvential area surrounding a blood vessel.

Description of the Related Art

It has been recognized that activity of the sympathetic nerves to thekidneys contributes to essential hypertension, which is the most commonform of hypertension. Sympathetic stimulation of the kidneys maycontribute to hypertension by several mechanisms, including thestimulation of the release of renin (which results in production ofangiotensin II, a potent vasoconstrictor), increased renal reabsorptionof sodium, at least in part related to increased release of aldosterone(which increases blood volume and therefore blood pressure), andreduction of renal blood flow, which also results in angiotensin IIproduction.

Since the 1930s it has been known that injury or ablation of thesympathetic nerves in or near the outer layers of the renal arteries candramatically reduce high blood pressure. As far back as 1952, alcoholhas been used for tissue ablation in animal experiments. SpecificallyRobert M. Berne in “Hemodynamics and Sodium Excretion of DenervatedKidney in Anesthetized and Unanesthetized Dog” Am J Physiol, October1952 171:(1) 148-158, describes applying alcohol on the outside of adog's renal artery to produce denervation.

Ablation of renal sympathetic nerves to treat hypertension has beenshown to be a successful strategy (e.g., Renal sympathetic denervationin patients with treatment-resistant hypertension (The Symplicity HTN-2Trial): a randomized controlled trial. Lancet 2010, 376:1903-1909).

However, in order for the procedure to be successful, renal nerves needto be sufficiently ablated such that their activity is significantlydiminished. This issue was likely a contributing factor in SimplicityHTN-3 Trial (e.g., Catheter-based renal denervation for resistanthypertension: rationale and design of the SYMPLICITY HTN-3 Trial. ClinCardiol. 2012; 35:528-535). In this study, incomplete ablation may haveserved as a key determinant in the negative study outcome. A significantdrawback of ablation procedures is the inability for the physicianperforming the procedure to ascertain during the procedure itself thatthe ablation has been successfully accomplished. The reason for this isthat the nerves cannot be visualized during the procedure; therefore,the procedure is be performed in a “blind” fashion. The ablationprocedure is invasive, requiring catheterization of the femoral artery,advancement of a catheter into the renal artery, administration ofiodinated contrast agents, and radiation exposure. Furthermore,procedural success with currently available devices is far fromuniversal. In spite of success in some patients as found in theSymplicity-HTN-2 Trial, it is noteworthy that 16% of patients failed toachieve even a 10 mmHg reduction in systolic blood pressure and 61% didnot achieve a goal systolic blood pressure of <140 mmHg.

The procedure is be performed in a catheterization laboratory oroperative-type suite. The benefit-risk, cost-benefit, and incrementalcost effectiveness ratio, of this invasive procedure would all beenhanced if measures related to procedural success could be assessedduring the procedure. Assessing the success, or sensing relevant data toguide the ablation procedure, during the surgery would allow thephysician to perform additional ablation interventions and/or to adjustthe technique as needed. This real-time assessment would be expected toimprove efficacy and to reduce the need to bring the patient back for asecond procedure at additional cost and risks to the patient.

The desired effect of renal sympathetic nerve ablation procedure is alowering of blood pressure, with consequent reduction in the need forchronic antihypertensive drug treatment. Since the blood pressurelowering effect of the treatment often does not occur immediately, theblood pressure measured in the catheterization laboratory cannot act asa measure to guide to the technical success of the procedure. What isclearly needed are systems and methods for assessing denervationprocedural success, for example, by stimulating the nerve fibers toassess whether the stimulation modulates a measurable quantity such asblood pressure or cardiac activity, or by directly recording nerveactivity from the from the target volume of tissue, or both (e.g.recording evoked activity that is time locked to stimulation).

There are currently two basic methods to ablate renal sympatheticnerves: a) energy-based neural damage resulting from radiofrequency orultrasonic energy delivery and b) chemical neurolysis. Both methodsrequire percutaneous insertion of a catheter into the renal arteries.Radiofrequency-based methods transmit radiofrequency energy through therenal artery wall to ablate the renal nerves surrounding the bloodvessel. Chemical neurolysis uses small gauge needles that pass throughthe renal artery wall to inject a neurolytic agent directly into theadventitial and/or periadvential area surrounding the blood vessel,which is where the renal sympathetic nerves entering and leaving thekidney (i.e., afferent and efferent nerves) are located.

Recent technology for renal denervation includes energy delivery devicesusing radiofrequency or ultrasound energy, such as Simplicity™(Medtronic), Vessix™. (Boston Scientific) EnligHTN™ (St. Jude Medical)and One Shot™ system from Covidien, all of which are RF ablationcatheters. There are potential risks using the current technologies forRF ablation to create sympathetic nerve denervation from inside therenal artery. The short-term complications and the long-term sequelae ofapplying RF energy from the inner lining (intima) of the renal artery tothe outer wall of the artery are not well defined. This type of energyapplied within the renal artery, and with transmural renal arteryinjury, may lead to late stenosis, thrombosis, renal artery spasm,embolization of debris into the renal parenchyma, or other problemsrelated to the thermal injury of the renal artery. There may also beuneven or incomplete sympathetic nerve ablation, particularly if thereare anatomic anomalies, individual variation in characteristics such aswall depth or distance of nerves from the inner wall, or atheroscleroticor fibrotic disease in the intima of the renal artery, the result beingthat there is non-homogeneous or otherwise ineffective delivery of RFenergy. This could lead to treatment failures, or the need foradditional and potentially dangerous levels of RF energy to ablate thenerves that run along the adventitial plane of the renal artery. Similarsafety and efficacy issues may also be a concern with the use ofultrasound or other type of energy used for ablation when this isprovided from within the vessel wall.

The Simplicity™ system for RF delivery, like other energy based systems,applies energy to the intimal surface of the artery in a spiral patternbecause intraluminal circumferential ablation would result in a higherrisk for permanent arterial damage leading to renal artery stenosis orperforation. The “burning” of the interior wall of the renal arteryusing RF ablation can be extremely painful during the procedure. Thelong duration of the RF ablation renal denervation procedure requiressedation and, at times, high doses of morphine or other opiates, andanesthesia, close to the levels used for general anesthesia, to controlthe severe pain associated with repeated burning of the vessel wall andits associated pain fibers. This is especially difficult to affect withany energy based system operating from inside the renal artery becausethe C-fibers, which are the pain nerves, are located within or close tothe media layer of the artery. Thus, there are numerous and substantiallimitations of the current approach using RF-based renal sympatheticdenervation. Similar limitations apply to ultrasound or other energydelivery techniques which are delivered from within the renal artery.

The Bullfrog® micro infusion catheter described by Seward et al in U.S.Pat. Nos. 6,547,803 and 7,666,163, which uses an inflatable elasticballoon to expand a single needle against the wall of a blood vessel,could be used for the injection of a chemical ablative solution such asguanethidine or alcohol but it would require multiple applications. Forexample, in one embodiment, the needle would be rotated within thearterial wall and then re-deployed in a new target area. Those Seward etal., patents do not describe or anticipate the circumferential deliveryof an ablative substance to provide ablation around the entirecircumference of the vessel. The greatest number of needles shown bySeward is two, and the two needle version of the Bullfrog®. would behard, if not impossible, to miniaturize sufficiently to enable thedistal end to fit through a small guiding catheter to be used in a renalartery, particularly if needles of adequate length to penetrate to theperiadventitia were used: this shortcoming is why the Bullfrog® isusually illustrated with one needle. Accordingly, the incorporation ofthree needles would likely be impossible to realize using the technologydisclosed in that prior art. If only one needle is used, controlled andaccurate rotation of any device at the end of a catheter is difficult atbest and could be risky, inaccurate, and therapeutically ineffective ifthe subsequent injections are not evenly spaced. This device also doesnot allow for a precise, controlled and adjustable penetration depth(i.e. relative to the wall surface) of delivery of a neuroablativeagent. The physical constraints regarding the length that can be used,thus limits the ability to inject agents to an adequate depth outside ofthe arterial wall, particularly in diseased renal arteries withthickened intima. All of these limitations could lead to incompletedenervation and treatment failure. Another limitation of the Bullfrog®is that inflation of a balloon within the renal artery can inducetransient renal ischemia during the operation and possibly late vesselstenosis due to balloon injury of the intima and media of the artery, aswell as causing endothelial cell denudation.

Jacobson and Davis in U.S. Pat. No. 6,302,870 disclose a catheter formedication injection into the interior wall of a blood vessel. WhileJacobson includes the concept of multiple needles expanding outward,each with a hilt to limit penetration of the needle into the wall of thevessel, his design depends on rotation of the tube having the needle atits distal end to allow it to get into an outwardly curving shape. Thehilt design shown of a small disk attached a short distance proximal tothe needle distal end has a fixed diameter which will increase the totaldiameter of the device by at least twice the diameter of the hilt sothat if the hilt is large enough in diameter to stop penetration of theneedle, it will significantly add to the diameter of the device. Using ahilt that has a greater diameter than the tube, suffers the disadvantagethat it increases the device profile, and also prevents the needle frombeing completely retracted back inside the tubular shaft from which itemerges This design requires keeping the needles exposed and potentiallyallowing accidental needlestick injuries to occur, during eithercatheter removal after the ablation procedure is completed, during anyrotation which is desired during the procedure, or when moving from onetarget location to the next. For either the renal denervation or atrialfibrillation application, the length of the needed catheter would makecontrol of such rotation difficult. Jacobson appears to intend the drugto be injected into the vessel wall rather than injecting exterior tothe vessel wall (at the targets nerve sites themselves) since the hilts,which limit penetration, are a relatively short fixed distance from thedistal end of the needles. Longer penetration depths that are needed toprovide the advantage of extending beyond the adventitia to the locationof the sympathetic nerves outside of the renal artery would greatlyincrease the diameter of the Jacobson catheter thereby making insertionof the catheter tip problematic and needlestick injuries even morelikely. There is also no mechanism that would provide for the adjustmentof penetration depth which may be important if the clinician wishes toselectively target a specific layer in a vessel or penetrate all the waythrough to the volume of tissue outside of the adventitia in vesselsthat may have different wall thicknesses. Many of the limitations ofJacobson may be due to the fact that Jacobson does not envision use ofthe injection catheter for denervation. It is also of note that FIG. 3of the Jacobson patent shows a sheath over expandable needles and doesnot disclose a guide wire. Further, the sheath has an open distal end.Both of these design limitations make advancement through the vascularsystem more difficult. Lastly, because of the hilts used by Jacobson, ifthe needles were withdrawn completely inside of the sheath they couldget stuck inside the sheath and be difficult to push out during theintended deployment at the target area. The above listed limitations andcomplexity of the Jacobson system might increase the risk of surgicalcomplications and inadequate, or incomplete, renal denervation.

McGuckin in U.S. Pat. No. 7,087,040 discloses a tumor tissue ablationcatheter having three expandable tines for injection of fluid that exita single needle. The tines expand outwardly to penetrate the tissue. TheMcGuckin device has an open distal end that does not provide protectionfrom inadvertent needle sticks from the sharpened tines. In addition,the McGuckin device depends on the shaped tines to be of sufficientstrength so that they can expand outwardly and penetrate the tissue. Toachieve such strength, the tines would have to be so large in diameterthat severe extravascular bleeding would likely often occur when thetines would be retracted back following fluid injection for a renaldenervation application. Further, there is no workable penetrationlimiting mechanism that will reliably set the depth of penetration ofthe distal opening from the tines with respect to the interior wall ofthe vessel, nor is there disclosed a preset adjustment for such depth.For the application of treating liver tumors, the continually adjustabledepth of tine penetration may make sense since multiple injections atseveral depths might be needed. However, for renal denervation, theability to accurately adjust the depth or have choice of penetrationdepth when choosing the device to be used can be important so as to notinfuse the ablative fluid too shallow and injure the media of the renalartery or too deep and thus miss the nerves that are in the adventitialand peri-adventitial layers of the renal artery.

Fischell et al in U.S. Pat. Nos. 8,740,849, 9,056,185, 9,179,962 andapplication Ser. Nos. 13/216,495, 13/294,439 and 13/342,521 describeapparatus and methods of using expandable needles to deliver ablativefluid into or deep to the wall of a target vessel. Each of theseapplications is hereby incorporated by reference in its entirety. Thereare two main types of embodiments of the above patents and patentapplications, those where the needles alone expand outwardly withoutsupport from any other structure and those with support structures suchas guide tubes that act as guiding elements to support the needles asthey are advanced into and/or through the wall of a target vessel. Thelimitation of the needle alone designs are that if small enough diameterneedles are used to avoid unwanted surgical results such as blood lossfollowing penetration through the vessel wall, then the needles may betoo flimsy to reliably and uniformly expand to their desired positions.The use of a cord or wire to connect the needles together in as shown inU.S. Pat. No. 9,056,185 helps some in the area. The use of guide tubesas described in the Fischell U.S. Pat. No. 8,740,849 and patentapplication Ser. Nos. 13/294,439 and 13/342,521 greatly improves thissupport, but the unsupported guide tubes themselves depend on their ownshape to ensure that they expand uniformly and properly center thedistal portion of the catheter. Without predictable catheter centeringand guide tube expansion it may be challenging to achieve accurate andreproducible needle penetration to a targeted depth. More recently inU.S. Pat. No. 8,740,849, Fischell et al describe self-expanding andmanually expandable ablation devices that have additional structures tosupport the needle guiding elements/guide tubes. Of these the preferredembodiment is the manually expandable design that will be the basis, atleast for illustration purposes and without intention of limiting thedisclosed invention, for the various embodiments of the presentinvention disclosed herein. The U.S. Pat. No. 8,740,849 designs for aPerivascular Tissue Ablation Catheter (PTAC) will be referencedthroughout this disclosure.

While the prior art has the potential to produce ablation of thesympathetic nerves surrounding the renal arteries and thus producedesired therapeutic effects such as reducing the patient's bloodpressure, none of the prior art includes sensors (e.g. extravascularsensors) or additional systems to monitor the activity of thesympathetic nerves being ablated. Such measurement would be advantageousas it could provide feedback related to the effectiveness of theablation procedure and indicate such as indicating if an additionalablation administration may be needed. For example, additional energydelivery or additional ablative fluid delivery or other type of ablationtreatment could be administered if sensed data obtained from sensorsoutside the vessel wall indicate the nerves were not ablatedsufficiently such may occur if the nerves are still conducting(electrical) activity.

It is technically feasible to measure renal sympathetic activitydirectly or indirectly in vivo using several methods. Such measurementshave been accomplished, for example in unrestrained conscious mice[Hamza and Hall, Hypertension 2012], dogs [Chimushi, et al. Hypertension2013], rats [Stocker and Muntzel, Am J Physiol Heart Circ Physiol. 2013]and rabbits [Doward, et al. J Autonomic Nervous System 1987].

In the study by Hamza and Hal, an electrode was surgically placeddirectly on the renal nerves and left in place while recordings weremade over up to 5 days. The recordings of renal sympathetic nerveactivity were confirmed by observations of appropriate responses toconditions of rest and activity, pharmacologic manipulation of bloodpressure with sodium nitroprusside and phenylephrine, and by neuralganglionic blockade. Doward, et al also used surgical placement of anelectrode to directly measure renal sympathetic nerve activity. Therecordings of renal sympathetic nerve activity were confirmed byobservations of appropriate responses to baroreceptor stimulation,angiotensin, central and peripheral chemoreceptors. In the study byChimushi et al., renal sympathetic nerves were stimulated from withinthe renal artery and evidence of activity was indirectly evaluated basedon blood pressure response to neural stimulation.

Throughout this disclosure the term perivascular space refers to thevolume of tissue radially outside of (or deep to) the media of a vesselof the human body such as an artery.

SUMMARY

The present application discloses, in some embodiments, a Nerve SensingCatheter (NSC) that senses perivascular renal sympathetic nerve activity(as an example although other types of extra-vascular nerve activity,including non-sympathetic nerves, may also be measured) and can be usedcomplementary to a non-sensing renal denervation device whether it is achemical device such as the PTAC of Fischell (e.g., U.S. Pat. Nos.8,740,849 and 9,056,185) or an energy delivery device such asSIMPLICITY®, or even when using external sources of ablation such assurgical intervention, or externally delivered energy such as focusedultrasound (such as the Surround Sound™ system of Kona Medical), etc.

Also disclosed is a perivascular Nerve Ablation and Sensing Catheter(PNASC). In one embodiment the PNASC is capable of delivering anablative fluid to produce circumferential damage in the tissue that islocated within the vessel wall, (e.g. the media of an artery) in theouter layer of the vessel (e.g. in the adventitia of an artery) orbeyond the outer layer of a vessel of a human body. The PNASC alsoincludes sensors for sensing the activity of nerves, such as thesympathetic nerves that lie outside of the external elastic lamina ofthe renal artery. The integrated PNASC has the advantage of saving timeat the cost of adding complexity to a device that was only designed toprovide ablation. The NSC requires a separate renal denervation devicebe used to provide ablation, but has a large potential market when usedin combination with other, potentially less effective and lesspredictable renal denervation devices, such as those that ablate nervesusing RF energy from intravascular sites. PNASC embodiments also aredisclosed that use, RF or ultrasonic energy to provide for perivascularnerve ablation, such as renal nerve ablation.

The nerve ablation procedure using perivascular injection of alcohol bythe prior art catheters disclosed by Fischell (e.g., the PTAC) or thePNASC disclosed herein, can be accomplished in a relatively short timeas compared with RF ablation catheters, and in some embodiments also hasthe advantage of using only a single disposable catheter, with noadditional, external, capital equipment. It will also, because ofreduced pain levels and shorter procedural time, provide the advantagessuch as permitting:

-   -   the use of short acting sedating agents like Versed,    -   delivery of local anesthetic into the adventitial space before        ablation and    -   the potential elimination/reduction of the need for large doses        of narcotics to counter patient discomfort and pain that are        typically experienced during RF energy based ablation        procedures.

Part of some embodiments of the present invention method for use of thePSNAC envisions that the pain associated with a chemical renaldenervation procedure can be either largely reduced or completelyeliminated by using ethanol as the ablative agent and also injecting theethanol slowly over a period no shorter than at least 10 seconds andideally longer than 30 seconds, which serves as a local analgesic at thesite of the renal nerves prior to its effect as an ablative agent. Thisprovides the advantage of decreasing the use of general anesthesia, andits associated risks and disadvantages, by providing for analgesia inthe region of ablation.

While the primary focus of use of PNASC is in the treatment ofhypertension and congestive heart failure by renal denervation, thePNASC has the ability to sense nerve activity such as sympathetic nerveactivity, and could also be used in conjunction with other renaldenervation devices to enhance the effectiveness of the renaldenervation or to provide additional denervation if the other device isnot appropriately effective.

In preferred embodiments, much of the structure of the NSC and PNASC maybe similar to the manually expandable PTAC designs shown in FIGS. 2through 11 of Fischell et al U.S. Pat. No. 8,740,849 incorporated hereinby reference. Specifically, the NSC and PNASC would use the similarproximal control structures as well as the same guide tubes and radialand lateral support structures.

Various versions of the NSC and PNASC will be included herein. In oneembodiment of the NSC the injector tubes with distal injection needlesof the PTAC of U.S. Pat. No. 8,740,849 are replaced by a solid sharpenedwire that is electrically insulated except for its tip that forms anelectrode. The proximal end of each wire connects through conductingmeans to electronic equipment (e.g., connected to wires at the proximalend of the catheter) used to monitor nerve activity sensed by theelectrodes and/or provide energy to the electrodes to ablate nervetissue.

For one embodiment of the PNASC, the PTAC structure shown in FIGS. 2-10of U.S. Pat. No. 8,740,849 would be modified to have the radiopaque wireinside the injector needles replaced by an electrode connected to aproximal insulated wire positioned within the distal end of theinjection needle. Ideally, the electrode would be of gold or platinum oranother radiopaque metal to provide radiopacity. At least twoconfigurations of this PNASC embodiment will be disclosed: one where theelectrode lies completely within the lumen of the injection needle and asecond embodiment where the electrode extends distally beyond the lumenof the injector tube and forms at least part of the sharpened needle. Itis also envisioned that with a separate control mechanism, these sensingelectrodes could be advanced through the distal end of the injectionneedles, further into the perivascular space. It can also be preferredto coat the inside of the distal tip of the PNASC injection needles toprevent the needle tip from shorting to the inside of the metallicneedle.

In this example embodiment each of the proximal insulated wires then runthrough the injector tube lumen into the lumen of the inner tube andfinally exit out of the catheter near the proximal end of the PNASC.There, the wires can be attached directly or through a connector to anelectronics module for any or all of the following:

-   -   providing energy for nerve ablation,    -   for sensing/measuring nerve activity directly or in response to        electrical stimulation and identifying changes that indicate        when successful or unsuccessful nerve ablation has occurred;        and,    -   for providing electrical stimulation energy at a lower voltage        or current than is used to provide nerve ablation.

The proximal exit for the wires may be though the side of the catheteror outward through the center of the injection port lumen where aTuohy-Borst fitting would seal around the wires with the side port inthe Tuohy-Borst used for infusion of the ablative fluid.

Sensing of the nerve activity may be done between pairs of electrodeslocated near or at the distal ends of the needles (PNASC) or wires (NSC)or between an active sensor located near or at the distal end of aneedle/wire and a reference electrode.

The reference electrode could be any electrical reference used toreference voltage or current measurements from the distal electrodesembodiments including:

-   -   a reference electrode located on the body of the PNASC/NSC,        including a ring located on the outside of the PNASC/NSC, a        portion of the distal nose of the PNASC/NSC, or an integrated        guide wire;    -   a separate guide wire; or,    -   an electrode placed on the body such as at a location over the        location of the renal artery.

The preferred embodiment would measure activity between pairs of distalelectrodes or would use the skin electrode (e.g., a standard ECGelectrode) as this will allow a smaller diameter configuration of theinternal lumen of the catheter.

Embodiments of the PNASC can have injection ports such as side holes inthe sensor/injector tube just proximal to the distal electrode orlongitudinal holes through the electrode. These holes allow ablativefluid injected from a proximal injection port in the handle of the PNASCto effuse from the distal end of each needle

In its embodiments, the PNASC, similar to the PTAC of U.S. Pat. No.8,740,849 is a percutaneously introduced catheter with two or moreinjection needles configured for the delivery of ablative fluid. Theneedles expand outwardly from the catheter and penetrate into or fullythrough the wall of the renal artery and into the perivascular spacewhere the sympathetic nerves are located.

Another embodiment of the PNASC could have one or more expandablestructures separate from the needles for fluid delivery. Thesestructures could be configured to deliver a sharpened wire forming adistal electrode through the arterial wall into the tissue beyond. Thecontrol of the expansion of these sharpened wires, which can provideenergy based ablation or nerve activity sensing, can occur either by thesame or separate mechanisms that expand and support the injectionneedles. For example, four guide tubes similar to those in the PTAC ofU.S. Pat. No. 8,740,849 could expand outwardly from the shaft of thePNASC catheter. Four sharpened structures would then be advanced throughthe guide tubes through the renal artery wall and/or into theperiadventitial space. Two of the four structures could be injectionneedles for delivery of ablative fluid and two could be sharpened wiresfor providing energy based ablation and/or nerve activity sensing theeffectiveness of the ablation. Preferably, in one embodiment, thesensors are circumferentially offset from the injection needles. In onetwo-needle embodiment, the offset is about 90 degrees, and in athree-needle implementation, the offset is about 60 degrees. This typeof “offset” configuration could be well suited for assessing ablationbecause the sensors are maximally separated from the injection needlesthat provide the therapy and so they are located where the effect of theinjection would be least evident. In other words, if the nerves areappropriately damaged as reflected by sensed data that is sensed bysensors located at the points furthest from the point of fluid injectionthen the nerves everywhere else around the ring of ablation should beadequately ablated. Configurations with more or less than 4 penetratingstructures can also be envisioned. Configurations with sensingelectrodes offset longitudinally from the injection needles are alsoenvisioned. Embodiments where the 4 needles serve both as sensor andablation elements (at different times) are also envisioned, and furtherthe sensing or ablation can utilize bipolar montages where the anode andcathode are located on the same conduit tip, or monopolar montages wherethe energy travels between needles or where the return electrode islocated elsewhere within/on the patient. Embodiments where combinationsof needle electrodes are activated for sensing and/or ablation insequential order is also envisioned. Further, embodiments in whichperivascular RF ablation is preceded or followed by injection of anablative or analgesic agent will be disclosed—it may be an advantage toutilize RF ablation followed by chemical ablation since the twomodalities of ablation may cover different regions of the target nervepathways.

A PNASC integrated ablation and sensing system may also provide largeadvantages over other current technologies for applications other thanrenal denervation as the PNASC provides a highly efficient, andreproducible perivascular circumferential ablation of the muscle fibersand conductive tissue in the wall of the pulmonary veins near or attheir ostium into the left atrium of the heart, or in the pulmonaryarteries in the case of nerve ablation to treat pulmonary arterialhypertension. Such ablation could interrupt atrial fibrillation (AF) andother cardiac arrhythmias. For the AF application, nerve and/or cardiacmyocyte electrical activity measurement could be an effective techniqueto provide immediate assessment of the success of an AF ablationprocedure. Other potential applications of this approach, such aspulmonary artery nerve ablation, or others, may also become evident fromthe various teachings of this patent specification.

Like the PTAC embodiments of U.S. Pat. No. 8,740,849, the NSC/PNASC ofthe present application can incorporate a small diameter catheter, whichincludes multiple expandable injector tubes having sharpened injectionneedles at or near their distal ends that are advanced through guidetubes designed to support and guide the needles into and/or through theinner layers of the target vessel. While this application concentrateson manually expandable versions of the NSC and PNASC, it is envisionedthat similar electrodes could be used with structures similar to theself-expandable embodiments shown in U.S. Pat. No. 8,740,849.

Some embodiments of the PNASC can also include any one, combinations, orall of the primary features of the self-expandable and balloonexpandable embodiments of the Fischell et al U.S. Pat. Nos. 8,740,849,9,056,185, 9,179,962 and application Ser. Nos. 13/216,495, 13/294,439and 13/342,521 including but not limited to:

Needle guiding elements/guide tubes to support the expandable injectionneedles.

Mechanical support structures to support the needle guiding elements,

A catheter body having less than 0.5 ml internal volume or dead space,

Radiopaque markers on the catheter, guide tubes and needles,

Penetration limiting mechanisms,

Depth of penetration adjustment mechanisms,

Proximal handle for control of catheter activation including aninjection port,

Matched radii of curvature between the injector tubes and guide tubes,

Methods including injection of an anesthetic agent before the ablation.

The NSC/PNASC devices would preferably have very small gauge needles(smaller than 25 gauge) to prevent unwanted surgical complications suchas extravascular blood loss following penetration and removal throughthe arterial wall. Also the PNASC, which includes a distal opening inone or more needles to provide egress for the ablative fluid, would havea preferred embodiment with the distal needle being non-coring(cutting). With a cutting needle the injection egress/distal openingports could be small injection holes (pores) cut into the sides of theinjector tubes or distal needle, proximal to the cutting needle tip. AHuber type needle is an example of such a non-coring needle. The PNASCwould also preferably have at least 2 injector tubes with distalneedles, but 3 to 8 tubes with distal needles may be more appropriatefor some applications. For example, the number and spacing of needlesmay be set depending on the diameter of the vessel to be treated and theability of the injected ablative fluid to spread within the perivascularspace. For example, in a 5-7 mm diameter renal artery, 3 needles shouldtypically be utilized if ethanol is the ablative fluid.

A preferred embodiment of the PNASC would use ethanol as the ablativefluid because this fluid is agrophobic, hygroscopic, lipophilic, andspreads quickly in the perivascular space. Therefore, only 3 needles aretypically needed to create approximately circumferential delivery ofthis ablative agent for a vessel of the size of a human renal artery.This allows the use of a smaller diameter and less expensive device thanwould be possible with 4 or more needles. It is also envisioned that useof ethanol or another alcohol plus another neurotoxic agent could alsoenhance the spread of the ablative agent in the perivascular space.

While this disclosure will show both NSC and PNASC embodiments whichinclude a fixed distal guide wire, it is envisioned that a separateguide wire could be used with the catheter designed to be either anover-the-wire configuration where the guide wire lumen runs the entirelength of the catheter or a rapid exchange configuration where the guidewire exits the catheter body at a proximal guide wire port positioned atleast 10 cm proximal to the distal end of the catheter and runs outsideof the catheter shaft for its proximal section. It is also envisionedthat one could use a soft and tapered distal tip, even without a distalguide wire, for some applications.

A fixed wire embodiment, or an embodiment with the soft tapered distaltip (without a guidewire), are preferred embodiments, as they would havethe smallest distal diameter. Just proximal to the fixed wire is atapered distal portion of the SNAC/PNASC that eliminates any sharpchange in diameter that could cause the catheter to snag duringadvancement into the vasculature of a human.

It is also envisioned that the wires leading to two or more of thedistal needle/electrodes could be attached at the proximal end of thePNASC to an electrical or RF source to deliver electric current or RFenergy to perform tissue and/or nerve ablation. This could provide anideal configuration for RF energy based renal denervation since theelectrodes deliver the energy outside of the medial layer of the renalartery, and the normal intimal and medial wall structures would becooled by blood flow. This configuration should dramatically reduce thedamage to the artery, and associated clinical complications, as comparedwith intraluminal RF ablation. Also important in some cases is that thesympathetic nerves to be ablated are quite deep beyond the outside ofthe media of the artery while the pain nerves are within or close to themedia. Therefore an energy based denervation from electrodes deep to theoutside of the media may be much less painful than energy based ablationprovided at sites inside of the renal artery. The electrical equipmentmay also include nerve activity sensing electronics.

It may be advantageous that the same electrodes used in a first mode toablate nerves or other tissue, are also used in a second mode toevaluate the electrical characteristics at the treatment site. Forexample, one could measure nerve activity to obtain baseline data,provide ablation treatment to the nerves with energy and subsequentlyconfirm the efficacy of the ablation by one or more post-ablation nerveactivity measurements. These measurements could then compare thedifference between the pre-procedure and post-procedure sensed data toat least one defined therapy efficacy criterion. If ablation was notsufficient since it did not meet the efficacy criterion then a secondaryablation treatment followed by a secondary post-ablation nerve activitymeasurement would be done to again assess whether the nerves aresufficiently ablated to meet at least one defined therapy efficacycriterion. This can obviously be continued until the one or more therapycriteria are met. Further, while accomplishing more than one ablationtreatment the catheter can be moved distally or proximally along thevessel, or rotated, so that the ablation treatment is applied to a newregion. This may be especially important in some embodiments when usingelectrical rather than chemical ablation since this type of ablation maybe more localized in its effects.

It is also envisioned that the PNASC device could be operated accordingto an ablation protocol to provide one ablation substance.Alternatively, more than one neuroablative substances can be injectedsequentially or simultaneously according to the ablation protocol. Theablation protocol can also define a sequence of injections configured toablate the target nerves, in order to optimize permanent sympatheticnerve disruption in a segment of the renal artery (neurotmesis). Theanticipated neurotoxic agents that could be utilized to provide ablationinclude but are not limited to ethanol, phenol, glycerol, localanesthetics in relatively high concentration (e.g., lidocaine, or otheragents such as bupivacaine, tetracaine, benzocaine, etc.),anti-arrhythmic drugs that have neurotoxicity, botulinum toxin, digoxinor other cardiac glycosides, guanethidine, heated fluids includingheated saline, hypertonic saline, hypotonic fluids, potassium chloride,cooled or heated neuroablative substances such as those listed above.

It is also envisioned that the ablative substance used for the ablationtreatment according to the ablation protocol can be hypertonic fluidssuch as hypertonic saline (extra salt) or hypotonic fluids such asdistilled water. These could cause damage to the nerves and could be aseffective as alcohol or specific neurotoxins. These can also be injectedhot, or cold or at room temperature. The use of distilled water,hypotonic saline or hypertonic saline with an injection volume of lessthan 1 ml eliminates one step in the use of the PNASC because smallvolumes of these fluids should not be harmful to the kidney.Accordingly, this obviates the need to completely flush the ablativefluid from the PNASC with normal saline to prevent any of the ablativefluid getting into the renal artery during catheter withdrawal. Thissystem and method provides the advantage that there would be only onefluid injection step per artery instead of two as would occur if a moretoxic ablative fluid were used during ablation.

It is also envisioned that the PNASC could be connected to a heatedfluid source to deliver high temperature fluids to ablate or injure thetarget tissue or nerves. The heated fluid could be normal saline,hypertonic fluid, hypotonic fluid alcohol, phenol, lidocaine, or someother combination of fluids. Injection of hot or vaporized normalsaline, hypertonic saline, hypotonic saline, ethanol, distilled water orother fluids via the needles could also be performed in order to achievethermal ablation of target tissue or nerves at and around the needleinjection sites.

The present disclosure also envisions use of anesthetic agents such aslidocaine before the ablation procedure begins in order to provide alocal anesthetic/analgesic to reduce or eliminate the pain associatedwith the denervation procedure.

Various scientific articles have described methods of measurement ofnerve activity, yet these have not disclosed obtaining measurementsperivascularly from a catheter with sensor that pierce the vessel wall.In a preferred embodiment of this application, external equipment may beprovided that interfaces with the proximal end of the catheter. Theexternal equipment may include a display of one or more electricalcharacteristics of sensed nerve activity such as the peak voltage,average voltage, peak power, average power, one or more bands of power,absolute spectral power, normalized power, inter-burst interval,characteristics of a low-frequency band or a high frequency band, or theratio between the two, relative spectral power, burst rate, burstduration, spike count, spike rate, correlation (either autocorrelationor correlation between data from 2 or more monopolar or differentialsensed channels), correlation of time waveforms or one or more ranges ofband-passed sensed activity, and/or coherence. The measurements can beevaluated over a time interval and summary statistics can be provided.

Further measurements may be categorized, sorted, time-locked,correlated, normalized or otherwise evaluated in relation to measuressuch as blood pressure, a component of the cardiac cycle, heart rate,and/or other measures of the sympathetic and parasympathetic system. Thedifference between measurements made before and after the provision of arenal denervation procedure can be used to assess the effectiveness ofthe procedure. Of these nerve measurements, the average voltage would bea preferred measurement. The external equipment could also include agraphical display of the actual sensed signals (after signalconditioning such as amplification and filtering). The electronicequipment can also allow a user to select and define at least one pairof electrodes that is being used to derive a signal that is displayed.For example, a switch control can be provided to enable a user to chooseelectrode-pair derivations such as 1-2, 2-3 or 3-1, where each electrodeis on a different conduit, would be desirable. Other derivations whereelectrode 1 is referenced to an electrode located distally within apatient could also allow electrical activity to be localized to a morespecific degree since the active electrode recording the activity wouldreflect nerve activity and the reference electrode would not.

Measurement may be made between two electrodes:

-   -   both in the perivascular space separated circumferentially,    -   both in the perivascular space separated longitudinally,    -   one in the perivascular space and one in the media of the        vessel,    -   one in the perivascular space and one on the intimal surface of        the vessel, or    -   one in the perivascular space and one in the blood stream on the        catheter surface.

Similar to the PTAC designs of U.S. Pat. No. 8,740,849 both PNASC andNSC devices of the present application, normally include the controlmeans in the proximal portion of the catheter that serves to limit theneedle/wire penetration of the vessel wall which occurs distally.Accordingly, the PNASC and NSC would include one or more manualcontrollers, such as handles similar to those shown in FIG. 11 of U.S.Pat. No. 8,740,849. In an embodiment, these controllers would be used bythe operator to cause first the expansion of the guide tubes and second,the advancement of the needles/electrodes. The reverse motion of thesecontrollers would then retract the needles/electrodes back into theguide tubes and then retract the guide tubes back into the catheter bodyor under a sheath. Mechanical locking mechanisms can be provided in thehandles or elsewhere to prevent accidental movement of the guide tubesand needles are also described by Fischell et al in U.S. Pat. No.8,740,849 and can be incorporated into the NSC and PNASC embodiments ofthis disclosure.

Similarly, U.S. Pat. No. 8,740,849 includes disclosure of a proximalsection with separate ports for flushing of the catheter lumen andablative fluid injection that may also be included in the embodimentsdisclosed in the present application which can have similar structuresand controls in the proximal section.

For both PNASC and NSC, conducting insulated wires provide conduction ofelectrical signals between distal electrodes/sensors and the externalequipment attached to the wires near the proximal end of the catheter.The insulated wires would typically run through the body of thecatheter.

The PNASC can have radiopaque markers to show, during fluoroscopy, theextension of the needles through the artery wall into theperiadventitial space. The NSC also can have radiopaque markers on thesharpened wires to show under fluoroscopy the extension of the wiresthrough the artery wall into the periadventitial space. In both PNASCand NSC, the sensor itself would likely be made of gold or platinum andserve as a radiopaque marker.

Another feature of the presently disclosed PNASC, that ties into thePTAC disclosed by Fischell in U.S. Pat. No. 8,740,849, is a design thatreduces the internal volume of the injection lumens of the catheter (the“dead space”). It is anticipated that less than 0.5 ml of an ablativefluid such as ethanol will be needed to perform PeriVascular RenalDenervation (PVRD). The dead space should be less than 0.5 ml andideally less than 0.2 ml. With certain design features it is conceivedthat the dead space can be reduced to less than 0.1 ml. Having theinsulted wires inside of the fluid injection lumen may further reducethe dead space volume. Such features include using a small diameter <0.5mm ID hypotube for the inner tube used for fluid injection for thePNASC, and/or designing the proximal injection port and or injectionmanifold at the proximal end of the PNASC to have low volume by havingsmall <0.5 mm inner diameter and a short, <2 cm length.

In both the PNASC and NSC devices, a wire attached to each distal sensorextends the entire length of the catheter and exits at or near theproximal end. In an embodiment this can occur with the wires exitingthrough a connector which permits electrical connection to anelectronics module. While the preferred embodiment has the insulatedwires running within the catheter body, it is also envisioned that thewires could be run outside of the catheter body.

The electronics module can include amplifiers for each sensor (ordifferential amplifiers for pairs of sensors), filters,analog-to-digital converters to digitize the signals and a centralprocessing unit with memory (CPU) to process the signals and presentmeasures related to nerve activity using a nerve activity visualdisplay. Nerve activity measurements can also be used to drive sonictransducers which provide auditory signals related to the nerve activityor the comparison of nerve activity to a treatment criterion. Auditoryfeedback and alarms may be provided based upon the measures and/or theirassessment in relation to treatment or safety criteria such asthresholds. The electronics module can be high level and allow senseddata from defined pairs of sensors to be displayed and actualmeasurements of nerve activity displayed. Alternatively, basic nerveactivity measurements can be reflected on a low level using a simple 5LED display for each sensor.

A calibrate button can be used by a user in order to operate acalibration module and to normalize the sensed “nerve activity level”which occurs during or after ablation in relation to baselinemeasurements made during initial measurement of sympathetic nerveactivity which occurred prior to ablation. In one embodiment, all 5 LEDscould be activated to show maximum activity. Following the renaldenervation procedure, the user could operate the electronics module tocause a post-therapy measurement to be obtained which can then becompared to the pre-therapy measurements. The reduction in nerveactivity between the pre-therapy measurement and the post-therapymeasurement would be displayed by illumination of the new level as anormalized value (e.g., if 4 of the 5 LEDs were lit, then the normalizedsensed activity would be in the 80% range (+/−10%) of the baselineactivity that occurred prior to ablation).

The therapy criteria might be defined as a reduction of the number ofdiodes that are lit, for example, 0, 1, or 2 out of 5. If the postdenervation level is 40% of the normalized level for one of the sensors,then only 2 of the 5 LEDs would be lit showing a 60% drop in nerveactivity. An example of even simpler version would have a green, yellowand red LED for various sensors. wherein this example, green indicatesnormal nerve activity (e.g., in relation to the pre-ablation baseline),yellow indicates a partial reduction and red indicates a significantreduction. In another embodiment, the range used for normal does notneed to be derived from a baseline sample for the patient can be a rangedefined as normal for the population (which can be a population normvalue that is adjusted according to demographic variables such as genderand age and may also be adjusted according to physiological measurementsof the patient such as blood pressure or according to medication takenby the patient). In another embodiment, instead of using lights, one canuse sounds, where a characteristic of the sound (e.g. tone) is increasedor decreased according to measurements made on the sense nerve activity.

In an embodiment that used a sensed baseline as a “control” level ofactivity a processor within the electronics can calculate an averagemeasurement of the sensed activity over at least one specifiedmeasurement time interval. The processor could then be configured tocompare the post-ablation sensed activity over a similar, or different(e.g. shorter), duration of nerve activity measurement which occursafter ablation therapy. The electronics of a sensing module can beconfigured to display a quantitative, numerical reduction value (e.g.,“Nerve activity reduced by 64% compared to baseline nerve activity.”)

As with many of the prior Fischell et al applications cited herein, itis an advantageous feature for certain embodiments of this inventionthat the guide tubes are needle guiding elements for the advancement ofthe ultra-thin injection needles or sharpened wires that are advancedoutwardly through the wall of the renal artery. Specifically, prior artsuch as Jacobson that describes curved needles that are advancedoutwardly from a central catheter to penetrate the interior wall of atarget vessel, have bare needles that are advanced on their own, andwithout structural support, from the distal end or the side of acatheter. Without additional guiding (support) during advancement,needles that are thin enough to not cause blood loss followingwithdrawal from the wall of the artery are generally too flimsy toreliably penetrate as desired into the vessel wall.

It is also advantageous to have the pre-set radius of curvature of theguide tubes and injection needles be matched as disclosed in FischellU.S. patents previously cited.

Thus it is envisioned that a key aspect of the small needle embodimentsdisclosed in the present application is the inclusion of needle guidingelements such as guide tubes that allow the ultra-thin injection needlesto be reliably advanced into the wall of a target vessel to the desireddepth. Such guiding elements need not be a tube or have a roundcross-section. For example, the structure support can be realized by ahalf or partial tube, or they can be a structure with a slot thatprovides a guide for the advance-able needles. A guiding structure couldbe any expandable structure such as a spring that expands outwardly andprovides radial support and/or a guide for the needles. The terms“expand” and “expands” are intended to refer to motion of a structurefrom a first position relatively closer to a longitudinal axis of thecatheter to at least a second position that is relatively farther awayfrom the longitudinal axis, whether the motion is by expansion,deflection, pivoting, or other mechanism. It is desirable that theneedle guiding elements expand outwardly from the central catheter.

What is also disclosed in the present application is the use ofadditional structures to provide radial and lateral support for theneedle guiding elements themselves as disclosed by Fischell in U.S. Pat.No. 8,740,849. This is desirable if one seeks a uniform penetration andangular spread of the multiple needles. In addition, as the needles areadvanced, and guided by the “guiding elements,” (e.g., the guide tubes)the guiding element can, if unsupported, back away from the desiredposition against the interior wall of the vessel. For this reason, thepresent disclosure like the PTAC of U.S. Pat. No. 8,740,849 includes thedesign of structures that provide radial (“backup”) support for theneedle guiding elements that provide resistance to the guiding elementsbacking away from the interior surface as the needles are advanced intothe wall of the vessel.

There are other medical conditions which may be adversely affected byinappropriate (intrinsic) neurological activity. Early studies suggestthat those patients who have undergone renal denervation (withradiofrequency ablation from inside the renal artery) may have improveddiabetes and even decreased apnea episodes (in those that haveunderlying Obstructive Sleep Apnea). Some embodiments of the presentinvention's ablation device (PNASC) can offer more selective andcomplete ablation. We believe that with the addition of the sensingcharacteristics of the catheter that we will be able to tailor thetherapy to the desired neuromodulated response.

Another potential application of the PNASC applies to COPD (ChronicObstructive Pulmonary Disease) that has a potentially reversiblecomponent often treated with sympathomimetic agents and also those thatdecrease (atropine like) parasympathetic tone. Current medical therapyhas significant side effects because of the systemic effects of thesemedications. Use of the PNASC (or PTAC of Fischell et al Ser. No.13/752,062) to provide focal ablation of parasympathetic system and/oraugmentation of the sympathetic system may allow these patients improvedpulmonary function without and with fewer oral or inhaled medications.

A feature of the present application is to have a NSC that ispercutaneously delivered with outwardly expandable sensors designed topenetrate into and/or through the renal artery wall into theperiadvential space where the sensors can be used with associatedexternal electronics to measure sympathetic nerve activity, includingchanges in the level of sympathetic nerve activity following a renaldenervation procedure. Such an NSC could be used with any renaldenervation system or device.

A feature of the presently disclosed PNASC is to have a percutaneouslydelivered catheter with expandable supported needle guiding elementsthrough which injection needles are advanced for injection of anablative fluid into or beyond the outer layers of the renal artery withsensing electrodes and associated external electronics to measuresympathetic nerve activity, including changes in the level ofsympathetic nerve activity following a renal denervation procedure.

Another aspect of the present application is to have an electronicsmodule external to the PNASC or NSC which amplifies the signal from thedistal sensors located in the perivascular space and provides a displayof nerve activity to allow the user to identify the effectiveness of thenerve ablation procedure such as a renal denervation procedure.

Still another aspect of the present disclosure is to have embodimentswith at least three guide tubes/needle guiding elements in the PNASCeach having a radiopaque marker. The guide tubes/needle guiding elementsbeing manually expandable outwardly from within a set of tubular shaftswhich provide additional support and backup to stabilize each guidetube/needle guiding element against the interior wall of the targetvessel. Expansion of the guide tubes/needle guiding elements isaccomplished by manipulation of a mechanism in the proximal portion ofthe catheter.

Yet another aspect of the NSC and PNASC of the present disclosure is toinclude one or more of the following radiopaque markers to assist inpositioning, opening, closing and using the PNASC. These include thefollowing:

A radiopaque ring marking the distal end of the outer tube;

Radiopaque markers at, or very close to the ends of the guide tubesusing either metal bands or plastic with a radiopaque filler such asbarium or tungsten;

Radiopaque markers on the distal portion of the injection needles orsharpened wires;

Radiopaque wires inside the lumen of the injector tubes and/or injectionneedles;

Wires of radiopaque metals such as gold or platinum to conduct thesignals from the distal sensors to the electronics module.

Making the sympathetic nerve sensing electrodes of a radiopaque materialsuch gold or platinum.

The distal fixed guide wire of the PNASC being radiopaque (e.g., usingplatinum wire);

There is provided in accordance with one aspect of the presentinvention, a catheter for sensing the activity of nerves outside of theinterior wall of a target vessel of the human body. The cathetercomprises a catheter body, having a central axis extending in alongitudinal direction and also having a central lumen. At least twoneedle guiding elements are provided, and adapted to expand outwardlytoward the interior wall of the target vessel. At least two needles,each needle having a distal electrode, are adapted to be advancedoutwardly guided by the at least two needles guiding elements, topenetrate the interior wall of the target vessel and advance furtherinto the tissue outside of the inside wall of the target vessel. Atleast two wires are provided for conducting signals sensed by at leasttwo electrodes, the wires connecting the electrodes to externalequipment outside of the catheter.

In one implementation of the invention, each needle guiding element is aguide tube, having a lumen, for receiving a needle therethrough. Thecatheter may include at least three needle guiding elements, threeneedles, and three insulated wires.

In accordance with another aspect of the invention, there is provided acatheter for sensing the electrical activity of extravascular tissue ata target site. The catheter comprises an elongate flexible body, and atleast one flexible extendable arm having a sharpened tissue penetratingtip carried by the body. The extendable arm is movable between a firstposition in which the tip is positioned within the body and a secondposition in which the tip is displaced radially outwardly from the bodyto penetrate tissue and reach the target site. An electrode is carriedby the extendable arm, and an electrical conductor extends through thebody and is in electrical communication with the electrode.

In one embodiment the catheter comprises three flexible extendable arms.Preferably, a needle support element in the form of a support tube orguide tube is provided for each flexible extendable arm. The supporttubes are movable between a first position within the body and a secondposition extending away from the body. The flexible extendable arms aremovable through the support tubes.

In accordance with a further aspect of the present invention, there isprovided a dual purpose catheter for both disrupting and evaluating theelectrical conductivity of a nerve. The disruption function is providedby application of electrical voltages between at least one pair ofelectrodes. Such voltages can produce electroshock, electrocautery or RFablation depending on the amplitude, duration, and frequency of thesignal and the material and structure of the electrodes.

In an embodiment, the dual purpose catheter comprises an elongateflexible body, and at least two tissue penetrating probes extendablelaterally from the body. A fluid effluent port is provided on eachprobe, each fluid effluent port in fluid communication with a fluidsupply lumen extending through the body. An electrode is carried by eachprobe, each electrode in electrical communication with a uniqueconductor extending through the body. Preferably, each tissuepenetrating probe is movably advanceable through a tubular support.

In accordance with a further aspect of the present invention, there isprovided a method of evaluating nerve ablation in a patient using acatheter system configured to provide sensing of nerve activity andelectronics configured for sensing, evaluation, and display of measuresderived from sensed data. The method comprises the steps of providing acatheter having an elongate flexible body with a proximal end, a distalend and a first electrode carried by the distal end. The first electrodeis movable between a retracted position within the catheter and anextended position for piercing a vessel wall. The electrode communicatessignals from the distal end along an electrically conductive conduit toa connector in the proximal end of the catheter which communicates withelectronics to provide sensing.

In embodiment of a method, the evaluation of sensed data includes a stepwherein the distal end of the catheter is positioned at an intravascularsite within the patient. The first electrode is advanced into the wallof the vessel, and an electrical characteristic of one or more nerves ismeasured. The measuring step may include placing the first electrode anda second electrode into electrical communication with electronicsincluding an instrument electrically coupled to the proximal end of thecatheter to receive data from at least the first electrode through theproximal end. The second electrode may be carried by the catheter andcan terminate in the proximal end of the catheter, or may be routedoutside of the catheter or simply be in contact with the patient's skin.

In accordance with a further aspect of the present invention, there isprovided a catheter system for energy based renal denervation from twoor more electrodes that are placed more than 2 mm deep to (radiallyoutside of) the location of the pain nerves of the renal artery so as toablate the sympathetic nerves that are radially outside of the arterialmedia while reducing the pain to the patient as compared with energybased denervation from inside of the renal artery.

There is provided in accordance with a further aspect of the presentinvention a catheter system for sensing nerve activity in the volume oftissue just outside of the vessel within the human body. The cathetersystem comprises electronic equipment designed to measure nerveactivity, a first electrode, and a second electrode. The first andsecond electrodes may be incorporated near the distal end of thecatheter, the catheter including a mechanism to position the distalelectrodes into the volume of tissue outside of the inside wall of avessel of the human body. The position of the electrode may be selectedto be a location in the outer layer of the vessel wall, or a location intissue that lies radially outside of the outer layer of the vessel (e.g.extravascular tissue). Conductive wires are adapted to connect the firstand second electrodes to the electronic equipment.

In accordance with alternative aspects of the invention, there areprovided methods and systems for treatment of extravascular/perivasculartissue such as denervation of renal nerves, while minimizing oreliminating pain to the patient from the ablation portion of theprocedure. Pain associated with first generation RF renal denervationdevices may be attributable to the nonspecific destruction of nervesassociated with the vessel wall. Pain is believed to be associated withdestruction of unmyelinated “C-fibers” which may run in or just outsideof the media (smooth muscle layer) of the vessel or in or just outsideof the external elastic lamina (outer skin of the media). Thesympathetic nerve fibers that affect blood pressure are predominantlythe “efferent” nerves that transmit signals from the brain to the kidneyand back. These nerves are believed to run almost exclusively in oroutside of the outer layer of the artery (the adventitia) and deep to(outside of) the external elastic lamina. Conventional intravascularenergy delivery by ultrasound or RF will ablate tissue from theendothelium (the inside layer) of the artery all the way to theadventitia, thus damaging both unmyelinated “C-fibers” causing pain aswell as a portion of the sympathetic nerve fibers. Intravascular energydelivery may be limited in efficacy as it is limited in its ability toablate the sympathetic nerves outside of the adventitia without causingirreparable damage to the artery.

As patients treated with the devices such as the PTAC of U.S. Pat. No.8,740,849 have been found to experience minimal or no pain duringinjection of ethanol into or outside of the adventitia (i.e., deep tothe pain fibers), delivering any type of ablative therapy (energy,chemical or other modalities) to the adventitia or outside of theadventitia should achieve both a better therapeutic ablation and do sowith minimal or no pain. It envisioned that when chemical ablation isperformed, a slow (>30 second) injection of the ablative fluid canprevent even the mild, short lived pain that may be felt from a fasterinjection because the fluid itself serves as an anesthetic. It isnoteworthy that locating the distal tip of the electrodes to locationsin the adventitia or outside of the adventitia not only increases theeffectiveness of ablative agents or energy that is delivered, but alsolocates the sensing electrodes in one or more locations that are nearthe relevant nerves in order to measure relevant nerve activity.

Thus, one aspect of the present invention provides a catheter forpreferentially denervating efferent nerves while sparing unmyelinatedC-fibers adjacent a target vessel. The catheter comprises an elongate,flexible catheter body having a central axis extending in a longitudinaldirection; at least two electrode guiding elements adapted to expandoutwardly toward the interior wall of the target vessel; at least twoelectrodes, each electrode having a distal uninsulated electrode tip,the at least two electrodes adapted to be advanced outwardly, guided bythe at least two electrode/needle guiding elements, to penetrate theinterior wall of the target vessel and position the electrode tipsbeyond the external elastic lamina.

In a preferred embodiment each electrode guiding element is a guide tubehaving a lumen. Each electrode may be advanced outwardly coaxiallythrough the lumen of a guide tube. At least three electrode guidingelements and three electrodes may be provided.

A catheter for localized RF ablation of extravascular tissue at a targetsite while sparing adjacent endothelium, comprises an elongate, flexiblebody; at least one flexible extendable arm having an electricallyconductive tip carried by the body of the catheter, the extendable armmovable between a first position in which the electrically conductivetip is positioned within the body of the catheter and a second positionin which the tip is displaced radially outwardly from the body topenetrate tissue of a target vessel and reach the target site, such thatthe electrically conductive tip is positioned completely beyond theendothelium of a target vessel. In a preferred embodiment, the catheterwill include at least three flexible extendable arms. A support tubemovable between a first position within the body and a second positionextending away from the body may be provided the flexible extendable armextends through the support tube.

One method of some embodiments of the present invention comprisesoperating a catheter system designed for preferentially denervatingefferent nerves while sparing unmyelinated C-fibers adjacent a targetvessel to treat hypertension while minimizing procedure discomfort. Themethod can comprise the steps of providing a catheter system having anelongate, flexible body with a proximal end, a distal end, and a firstelectrode carried by the distal end, the first electrode movable betweena retracted position within the catheter and an extended position forpiercing a vessel wall; positioning the distal end of the catheter at anintravascular site within the patient; advancing the first electrodeinto the vessel wall at a puncture site; and denervating tissue at afirst depth deep to (outside of) the external elastic lamina topreferentially denervate efferent nerves while sparing unmyelinatedC-fibers at a second depth near to or within the external elasticlamina, the second depth less than the first depth.

It is also envisioned that the method above can include using theelectrodes to sense electrical activity primarily from the efferentnerves and this may occur both before and after ablation so that thesensed data may be evaluated to determine the efficacy of the ablation.

Another aspect of the method of minimizing pain during renaldenervation, comprises the steps of advancing a distal end of a cathetertransluminally to a site in a renal artery; advancing an ablationelement from the catheter, through the media and into the adventitia;and ablating tissue within the adventitia while sparing the media. Theablation element may dispense an ablative fluid delivered from aneffluent fluid port. Alternatively, the ablation element may comprise anenergy delivery element including at least one of a: radiofrequency(RF), microwave, cryogenic, ultrasound, electrocautery, or heatingelement.

In any of the foregoing, the ablative element (e.g., conductive surfaceof an electrode; fluid from an effluent port) is preferably carried bythe catheter such that it can penetrate the vessel wall from inside ofthe vessel and position the ablative element to enable it to selectivelyablate tissue at a depth of at least about 3 mm, preferably at leastabout 5 mm and in some embodiments at far as 10 mm into the vessel wallfrom the endothelium in the direction of the adventitia, so that it canablate nerves in and outside of the adventitia minimizing damage to thenerves in or near the media. Preferably the catheter permits bloodperfusion through the renal artery during the ablation and/or nerveactivity sensing procedures.

An additional reason perivascular energy based ablation will be moreeffective than intravascular is that it is less damaging to the mediathat will be cooled by the significant blood flow through the artery,while there is much less cooling in the perivascular space.

One additional aspect of some embodiments of the present invention PNASCthat can provide both RF ablation and medication delivery, is that ananesthetic such as lidocaine could be injected before the RF ablationprocedure to also provide minimal or no pain to the patient during nerveablation.

The terms sensor and electrode may be used interchangeably here todescribe a conducting electrical contact which forms the distal end ofthe conduit 20. The terms sharpened wire and needle may be usedinterchangeably to refer to a sharpened distal portion that penetratesthe through a vessel or artery.

The catheter based system of the present disclosure can, in someembodiments, be varied, either by using hollow or solid conduits, andalso by adjusting the equipment (e.g., to provide delivery of ablativeor anesthetic fluid) and electronics (e.g., for proving sensing,stimulation, and or ablation) that are operated at the proximal end ofthe catheter. In various implementations the catheter system can serveas, in some embodiments, at least one of the following novel embodimentsto provide advantages over the prior art:

-   -   a sensing catheter system that can provide sensing that is used        to assess ablation provided by a treatment catheter configured        to provide ablation such as by RF, ultrasound, or ablative        fluid;    -   the catheter system of (a), further configured to provide        non-ablative stimulation in order to provide a stimulus for        obtaining sensing of evoked data that is time-locked to the        stimulus;    -   the catheter system of (a) configured with hollow, rather than        solid, conduits in order to provide local anesthetic such as        lidocaine;    -   a catheter system that can provide both sensing and ablation,        wherein the ablation treatment is provide by RF, ablation fluid,        or ultrasound;    -   the catheter system of (d), further configured to provide        non-ablative stimulation in order to provide a stimulus for        obtaining sensing of evoked data to measure the health of the        sympathetic nerve that is time-locked to the stimulus;    -   a catheter system configured with hollow rather than solid        conduits in order to provide local anesthetic such as lidocaine        and also energy based ablation by ultrasound or RF based        ablation;    -   a catheter system of a to f, configured to provide at least one        of sensing, stimulation, and ablation in a monopolar or bipolar        fashion using at least one distal tip of a conduit;    -   a catheter system of a to f, configured to provide at least one        of sensing, stimulation, and ablation using conduits that pierce        the inner wall to reside in the perivascular space outside of a        renal artery of a patient; and,    -   a catheter system configured to provide ultrasonic stimulation        using a stimulation element residing, at least in part, in the        perivascular space outside of a renal artery of a patient.

In order to realize these features and advantages, there will bedisclosed a number of main embodiments of the catheter systemsincluding:

Nerve Sensing Catheter (NSC) 10, which utilizes solid conduits at thedistal tip of the catheter;

Nerve Sensing Catheter NSC 100, which utilizes hollow conduits at thedistal tip of the catheter;

-   -   perivascular Nerve Ablation and Sensing Catheter PNASC 200;    -   perivascular Nerve Ablation and Sensing Catheter PNASC 400; and,

Ultrasound Nerve Ablation catheter UNAC 600. In some embodiments, alsodisclosed herein is a catheter for sensing the activity from nervesoutside of the lumen of a target vessel of a human body. The cathetercan include a catheter body having a distal end for insertion into apatient, a proximal end for controlling the movement of at least oneneedle, and a central axis extending in a longitudinal direction. Thecatheter can also include a connector configured to connect to externalelectronic equipment outside of a proximal end of the catheter. Theequipment can have a sensing subsystem configured for sensing localnerve activity within a patient, and can be configured to be connectedto at least one additional electrode in electrical contact with thepatient. The catheter can also include at least one needle guidingelement adapted to expand outwardly from the catheter body toward theinterior wall of the target vessel. The catheter can also include atleast one needle, the needle having at least one distal electrode, theneedle adapted to be advanced outwardly, guided by the at least oneneedle guiding element to penetrate and advance through the interiorwall of the target vessel into the tissue outside of the vessel lumen.The catheter can also include at least one wire for conductingelectrical signals between the at least one electrode and the connectorfor communicating with said external electronic equipment.

In the specification that follows, the term conduit will mean astructure in a catheter that can be utilized to transmit electricalenergy and/or fluid between a proximal end of the catheter and tissuewithin a human body.

Throughout this specification the terms injector tube with distalinjection needle is used to specify a tube with a sharpened distal endthat penetrates into tissue and is used to inject a fluid into thattissue. Such a structure could also be called a hypodermic needle, aninjection needle or simply a needle. In addition, the terms element andstructure may be used interchangeably within the scope of thisapplication.

The term Luer fitting may be used throughout this application to mean atapered Luer fitting without a screw cap or a Luer Lock fitting that hasa screw cap.

The term needle will be used throughout this disclosure to characterizea small diameter sharpened wire or tube designed to penetrate throughthe wall of a target vessel, its primary characteristic being asharpened tip. Thus the distal portion of the sharpened wire asdisclosed herein is also a needle.

Any of the terms ablative fluid, ablative solution and/or ablativesubstance will be used interchangeably to include a liquid, gel,suspension, or a gaseous substance delivered into a volume of tissue ina human body with the intention of damaging, killing or ablating nervesor tissue within that volume of tissue.

Also throughout this specification, the term inside wall or interiorsurface applied to a blood vessel, vessel wall, artery or arterial wallmean the same thing which is the inside surface of the vessel wall, orthe “intimal” surface of the vessel lumen.

Also the term injection egress is defined as the distal opening in aneedle from which a fluid being injected will emerge. With respect tothe injection needle, either injection egress or distal opening may beused here interchangeably.

The terminology “deep to” a structure is defined as beyond or outside ofthe structure so that “deep to the adventitia” refers to a volume oftissue outside of the adventitia of an artery.

These and other features and advantages of this invention will becomeobvious to a person of ordinary skill in this art upon reading of thedetailed description of this invention including the associated drawingsand the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of the distal portion of an NSC which usesthree expandable sharpened wires in its open position as it would bewhen manually expanded for measurement of the activity of nerves such asthe sympathetic nerves outside of the renal artery.

FIG. 2 is a longitudinal cross-section of a distal portion of the NSC ofFIG. 1 in its open position.

FIG. 3 is an enlargement of region S3 of the NSC of FIG. 2.

FIG. 4 is an enlargement of region S4 of the NSC of FIG. 2.

FIG. 5 is a longitudinal cross-section of the central portion of the NSCshowing the three proximal hypotubes.

FIG. 6 is a schematic view of the distal portion of either the NSC orPNASC both of which use three expandable NITINOL tubes with distalelectrodes that act as sensors for nerve activity. The view shows theNSC or PNASC in the open position following manual expansion.

FIG. 7 is a longitudinal cross-section of a distal portion of the NSC ofFIG. 1 in its open position.

FIG. 8 is an enlargement of region S8 of the NSC of FIG. 2.

FIG. 9 is an enlargement of region S9 of FIG. 8.

FIG. 10 is a transverse cross section at 10-10 of FIG. 9.

FIG. 11 is an enlargement of region S11 of the NSC of FIG. 7.

FIG. 12 is a longitudinal cross section of another embodiment of thedistal portion of the artery penetration portion of the NSC.

FIG. 13 shows a modification of the distal portion of FIG. 12 thatmodifies the NSC design into a PNASC design by the addition of sideholes for fluid injection into the perivascular space.

FIG. 14 is a longitudinal cross section of yet another embodiment of thedistal portion of the PNASC of FIG. 8 that would replace the embodimentof the distal needles shown in FIG. 9.

FIG. 15 is a longitudinal cross-section of the central portion of theNSC/PNASC showing the three proximal hypotubes.

FIG. 16 is a schematic view of the mechanisms at the proximal portion ofthe NSC/PNASC.

FIG. 17 is a longitudinal cross section of the PNASC configured forproviding ultrasound-based nerve ablation.

FIG. 18 is an enlargement of section S18 of FIG. 17.

FIG. 19 is an enlargement of section S19 of FIG. 17.

FIG. 20a is a schematic view of a method for using the PNASC.

FIG. 20b is a schematic view of an alternative method for using thePNASC.

FIG. 21 is a schematic view of the electronics that provide stimulationand/or sensing at the proximal portion of the NSC/PNASC.

FIG. 22 shows the modules through that may be included in the programmemory of the electronics.

DETAILED DESCRIPTION

FIG. 1 is a schematic view of the distal portion of a Nerve SensingCatheter (NSC) 10 that is designed to sense electrical energy (currentsor voltages) from extra-vascular tissue within a human body. In someembodiments the NSC may also deliver electrical energy to tissue, forexample, to provide for obtaining and assessing evoked activity. The NSC10 is shown in its open position, showing an inner tube 11, middle tube12, outer tube 13, outer tube extension 14 having distal openings 15through which the guide tubes 30 with radiopaque markers 36, distal tip34 and outer layer 32 are advanced outwardly from the body of the NSC10. Also shown is the tapered section 16 and fixed guide wire 40 withdistal tip 42. The NSC includes three conduits 20 with outer insulation22, and sharpened wire 24, with 2 of the three guide tubes and conduitsshown in their fully deployed positions (the third is not shown).Ideally the sharpened wires 24 are made from or coated with a radiopaquematerial such as gold or platinum.

The conduits 20 run all the way to the proximal end of the NSC 10 wherethey interface with electronic equipment 500 that provides sensing (asshown in FIG. 21). The distal tips 24 of the conduits 20 are shown herein the distal portion of the NSC 10. The conduits 20 extend through thecatheter body within the lumen of the inner tube 11. The insulation 22that insulates the conduits within the catheter body does not extendaround the most distal portion of the conduit 20 since this portionterminates as a sharpened wire/needle 24 which will penetrate thevascular wall and act as an electrode for sensing nerve activity from aperivascular location.

For purposes of illustration, the conduits 20 of FIGS. 1-5 are realizedas solid insulted wires, while the conduits of FIGS. 6-11 are realizedas hollow tubes, with the understanding that the two variations of theembodiments should not be considered limiting and may be realizedapproximately interchangeably, or both may be incorporated into variousembodiments, to realize advantages disclosed herein without departingfrom the scope of the invention.

The openings 15 in the distal portion of the catheter support the guidetubes 30 as the guide tubes 30 are advanced outwardly in order toprovide structural support during the subsequent deployment of theconduits 20. Although the NSC 10 of FIG. 1 has three guide tubes 30, itis envisioned that other embodiments could have as few as one or as manyas eight guide tubes with an optimum number typically being three orfour in the case of renal denervation. A larger diameter target vesselmight suggest the use of as many as 4 to 8 guide tubes 30 and conduits20.

As the different embodiments of the present invention are disclosed, itwill become evident that in addition to providing electricalconductivity from the proximal end of the NSC to the distal sharpenedwires 24, the conduits 20 may be adapted to be hollow to also provide apassageway for fluid injection near the tip of the sharpened wires 24. Amodified version of the NSC is disclosed herein, that provides bothnerve sensing and nerve ablation capabilities. This dual functioncatheter will be called a Perivascular Nerve Ablation and SensingCatheter (PNASC). In embodiments, the modifications can include:

Providing both electrical sensing and stimulation using the sharpenedwires 24 which act as electrodes to both sense nerve activity andprovide energy to tissue;

Providing electrical energy such as RF to the sharpened wires 24 thatact as electrodes provide energy based ablation;

Having a fluid passageway in the conduits 20 with an egress near thedistal end of the sharpened wires 24 for injection of an ablative fluidfor chemical nerve ablation and or dispensing an anesthetic/analgesicagent such as lidocaine; or

Providing an ultrasound transducer either within the body of the PNASCor in the distal portion of the conduits 20 to provide energy basedablation, such as ablation at perivascular sites that is delivered bythe conduits 20.

Different shapes are envisioned for the distal openings (or windows) 15in the outer tube extension 14 where the guide tubes 30 exit. Thesepossible shapes include and oval or round shapes such as a racetrackdesign with curved (e.g., round) proximal and distal ends and straightsides in the axial direction. It is also envisioned that there could bea movable flap (not shown) covering each opening 15, or a slit thatcould be opened to make the outer surface of the NSC smooth for betterdelivery through a guiding catheter into the renal artery. Such amoveable flap could be operated under the control of the catheter handlein the proximal section of the catheter. The mechanical operation of thecatheter can function so that the flaps are retracted prior to the guidetubes 30 being deployed. Alternatively the flaps may be made flexibleand soft enough that these are simply pushed aside by the guide tubes 30upon deployment.

It is a feature of this invention that the guide tubes 30 serve asneedle (i.e., conduit) guiding elements that provide structural supportfor the ultra-thin conduits 20. Specifically, prior art such as Jacobsonthat describe curved needles that are advanced outwardly from a centralcatheter to penetrate the wall of a target vessel, have needles that areadvanced on their own (naked) from the distal end or side of a catheter.Without additional guiding and support during advancement,needles/sharpened wires that are thin enough to essentially eliminatethe risk of bleeding following penetration and withdrawal from the wallof the artery are generally too flimsy to reliably penetrate as desiredinto the vessel wall. Thus it is envisioned that the NSC 10 of thepresent application preferably includes needle-guiding elements such asthe guide tubes 30 that allow the ultra-thin conduits 20 to be reliablysupported and advanced into the wall of a target vessel to the desireddepth. The guiding elements also serve to center the catheter within thevessel and to promote reliable, similar, and measured deployment of allthree sharpened wire tips 24 through the vessel wall.

As shown in FIG. 1, the three conduits 20, sensors 24 and guide tubes 30are spaced uniformly around the circumference of the catheter 10 atapproximately 120 degrees separation. The uniform spacing improves thesensing performance of the NSC 10. It is also envisioned that thespacing might be non-uniform for example two might be 50 degrees whilethe third could be 155 degrees from either of the first two.

In an alternative embodiment to that shown in FIG. 1, a catheter forsensing the activity from nerves outside of the lumen of a target vesselof a human body can only include one conduit 20. For the single conduit20 embodiment, a portion of the body of the NSC 10 such as the outertube extension 14 will typically be pushed against the inside wall ofthe artery diametrically opposed to the contact point where the needleguiding element/guide tube 30 expands outward to contact the wall of theartery.

FIG. 2 is a longitudinal cross-section of a distal portion of the NSC 10as shown in FIG. 1. The proximal portion of this figure shown on theleft side shows the three concentric tubes, the outer tube 13, middletube 12 and inner tube 11 which form the central portion of the NSC 10.The outer tube 13 is attached at its distal end to the outer tubeextension 14 which is in turn attached to the tapered section 16. Thefixed guide wire 40 with core wire 42 and outer layer 44 extends pastthe distal end of the tapered section 16. It should be noted that onlypart of the length of the guide wire 40 is shown in FIG. 2, its fulllength is shown in FIG. 1. Enlargements of the sections S3 and S4 ofFIG. 2 are shown in FIGS. 3 and 4 respectively.

FIG. 2 shows two of the three guide tubes 30 with outer layer 32, distaltip 34 and radiopaque marker 36 in their fully deployed positions asadvanced through the openings 15 in the outer tube extension 14. Theinterior surface of the outer tube extension 14 forms part of thetubular shaft 21 that lies within the outer tube extension 14 and whichis preferably made from a stiff material such as a high durometerplastic or metal so that the shaft 21 will be relative rigid as theguide tubes 30 are advanced and retracted.

Coaxially within the lumen of the guide tube 30 is the conduit 20comprising an insulated outer layer 22A and core wire 24 with theexposed sharpened distal tip portion 24. The uninsulated distal portionof the core wire 24 forms the electrode 25 which acts as a sensor. Asensor may operate either in combination with either or both of theother two electrodes 25 at the ends of the other two conduits 20, forexample, the first electrode/sensor 25 can be active and can bereferenced to the second or third electrode 25 using a differentialamplifier of the electronics. The electronics may be used to selectwhich combination of sensors is used during sensing or for stimulationto measure evoked nerve activity as well as whether other sensors (notshown) in other areas may be used to obtain sensed data. The core wires24 are ideally made from a memory metal such as NITINOL or a stiffspringy material such as stainless steel or “L605” which is a cobaltchromium alloy. While L605 is a fairly radiopaque material, if NITINOLor stainless steel is used, the distal portion of the wire 24 should becoated, at least in part, in a radiopaque material such as gold,platinum or tantalum.

A sensor 25 may be referenced to a distally located electrode that is inelectrical communication with the patient in order to provide monopolarsensing in relation to the renal nerve activity recorded from the distaltip sensor 25. It is well known to those skilled in the art that varioussensing montages may be implemented, but the advantage of the currentinvention is that one or more sensors can be used to measure nerveactivity of the sympathetic nerves while located in the perivascularspace outside of a renal artery of a patient after being deployed froman intravascular location.

In one configuration of the NSC, nerve sensing is performed in aresponsive method where one or more electrodes 25 may be used to provideboth non-ablative electrical stimulation and also sensing in order toassess evoked, “time-locked”, or “synchronized” nerve activity, or toprovide nerve stimulation in order to evoke a different type of changewhich may be assessed, for example, by a distally located sensor (e.g.,a blood pressure or distally located ECG sensor).

When the catheter system is configured as a PNASC for electricalablation, then the electrodes 25 can be configured to provide eitherbi-polar or monopolar electrical energy delivery.

The central portion of the NSC 10, which is more proximal than theportion labeled S4, is shown in FIG. 5.

As shown in FIG. 3, the central buttress 19 shown in FIG. 2 supports theguide tubes 30 both as these are pushed distally and after they arefully deployed. This central buttress 19 also provides radial supportfor the advanced guide tubes 30 that prevents the guide tubes 30 frombacking away from the interior wall of the target vessel as the conduits20 are advanced through the guide tubes 30 forward and the electrodes 24arrive at their desired positions such as in the periadventitial space2-10 mm beyond the interior wall of the target vessel. Additionallateral support for the guide tubes 30 are provided by the sides of theopenings 15 that, in combination with the central buttress 19, provideboth radial and circumferential/lateral support. The support can in someembodiments be advantageous both during guide tubes 30 advancement andtheir outward expansion as well as providing additional support duringdelivery of the injection needles of the conduits 20 through theinterior wall of the target vessel. The buttress may comprise adeflection surface such as a curved or linear ramp, which may, in acurved embodiment, correspond to the curvature of the outer surface ofthe guide tubes 30.

In one configuration, another feature of the NSC 10 (or the PNASCmodified versions) is that each conduit 20 is biased to have a centralaxis with the same, or nearly the same, radius of curvature as thecentral axis of its corresponding guide tube 30 when measured in anunconstrained state. In addition, the length of the guide tubes 30 ispreferably at least as long as the distal curved portion of the conduits20. This design constrains the curved portion of each conduit 20 withinthe lumen of the guide tube 30 so that the conduit 20 cannot twist orchange position.

An example of a design for the distal portion of the central buttress 19is shown in greater detail in FIG. 17 of U.S. Pat. No. 8,740,849.

As seen in FIG. 2 the plastic cylinder 17 attaches the inner tube 11 tothe three conduits 20. The inner tube 11 and plastic cylinder 17 canslide along the longitudinal axis of the NSC 10 inside of the middletube 12 which is shown with uniform diameter over its length includingthe portion coaxially outside of the plastic cylinder 17. The middletube 12 attached to the guide tube connectors 18 under the control ofthe catheters handle mechanisms to cause the advancement and retractionof the guide tubes 30. The inner tube 11 attached to the plasticcylinder 17 under the control of the catheters handle mechanisms tocause the advancement and retraction of the conduits 20.

FIG. 3 is the enlargement of section S3 of the longitudinalcross-section of the NSC 10 as shown in FIG. 2. FIG. 3 shows the detailsof the guide tubes 30 with interior layer 38, outer layer 36, distal end34 and radiopaque marker 32. Coaxially within the lumen of the guidetube 30 is the conduit 20 with insulated outer layer 22A and core wire24 with needle tip 23. The uninsulated distal portion of the conduit 20which is the core wire 24 forms the electrode 25 for sensing nerveactivity such as sympathetic nerve activity in the perivascular spaceoutside of the renal artery. The other two of the three conduits 20 alsohave their own respective insulated layers 22B (shown in cross sectionfor a different injection needle) and 22C (not shown). Radiopacity ofthe tip of each of the conduits 20 can in some embodiments be importantso that it can clearly be seen that the needle tips 23 are situated inan intended location such as in the perivascular space. This can beaccomplished by using a dense metal such as gold or platinum for thecore wire 24 or by attaching a radiopaque marker at or near the tip 23of the core wire 24. Plating the needle tip 23 with gold could also beeffective.

The guide tubes 30 are advanced out of, and retracted back into, thetubular shaft 21 through distal openings 15. In one embodiment, thethree guide tubes 30 are attached to each other near their proximal endsby the guide tube connector 18. FIG. 3 also clearly shows how the guidetube 30, when advanced against the central buttress 19 is forcedoutwardly and is supported by the curved ramp 29 of the central buttress19 as well as the sides of the opening 15 of the tubular shaft 21. Thecentral buttress 19 also has proximal fingers 27 that provide additionallateral support for the guide tubes 30.

The outer tube extension 14 connects at its distal end 14 a to thetapered section 16 which in turn lies coaxially around the guide wire 40with core wire 42 and outer layer 44.

Also shown in FIG. 3 is the penetration depth L1 which is the distancefrom the distal end of the guide tube 34 to the distal end 23 of thecore wire 24. Mechanisms at the proximal section of the NSC 10 (e.g.,the proximal handle 300, as shown in FIG. 16) control the motion of thedistal components of the NSC 10 including the guide tube 30 and theconduits 20. In one embodiment, the proximal section also includes themechanisms to limit and/or adjust the penetration depth L1 of the distalend 23 of the conduits 20. In another embodiment the proximal sectionalso includes mechanisms to adjust the deployment length of the guidetubes 30 similar to the mechanisms used to adjust or limit the depth ofpenetration of the conduits 20 beyond the distal end of the guide tubes30.

It is envisioned that the central buttress 19 and distal openings 15can, as shown in FIG. 3, be separate components of the NSC 10 or theycan be formed as a single molded or machined part as is shown in FIG. 17of Fischell et al U.S. Pat. No. 8,740,849. The distal tip 45 of thecentral buttress 19 provides the attachment to secure the buttress 19 tothe tapered section 16. Additionally, the buttress 19, distal openings15 and tapered section 16 could be a single molded or machinedcomponent.

While a preferred embodiment of the NSC 10 has the guide tubes 30 with apre-formed curved shape, flexible naturally straight guide tubes arealso envisioned where the buttress 19 forces the straight guide tubes tocurve outwardly for extension through the interior wall of the targetvessel.

While the term “central buttress” will be used herein, the key functionof the buttress 19 is the deflection surface such as ramp 29 thatprovides both radial and lateral support for the deployed guide tubes30. Specifically, the curved ramp 29 of the buttress 19 supports andguides the outward motion of the guide tubes 30 as they exit though thedistal openings 15 and also provides radial support for the guide tubes30 and conduits 20, as they come into contact with (engage) and thenpierce through the interior wall of the target vessel. Additionallateral support is provided by the fingers 27 of the central buttress 19and the sides of the tubular shaft 21 and sides of the openings 15. Suchlateral support ensures that the guide tubes move radially outwardwithout deflections in the circumferential (transverse to thelongitudinal axis of the catheter) direction.

While the central buttress 19 shown in FIG. 3 is a plastic part, aradiopaque metal part, such as stainless steel, or a coating, or aplastic material that includes radiopaque filler such as tungsten couldbe advantageously employed for showing the exact location where theguide tubes 30 will exit the NSC 10. It is also envisioned that aradiopaque marker could be attached to a portion of the openings 15 orbuttress 19 or outer tube extension 14 to show the likely spot where theguide tubes 30, and thus the conduits 20, would engage the interior wallof the target vessel.

Many of the components of the NSC 10 are typically made from plasticmaterials such as polyamide, polyurethane, nylon or tecothane. Theseinclude the outer tube 13, middle tube 12 and inner tube 11, the outertube extension 14, inner layer 38 and outer layer 36 of the guide tubes30, the tapered section 16, the buttress 19, the guide tube connector 18and the plastic cylinder 17. The plastic cylinder 17 (shown in FIG. 2)can be a molded part or be epoxy or another resin that is injected toaffix the conduit wires 20 together within the lumen of the inner tube11.

It is also envisioned that any or all of the inner tube 11, middle tube12 or outer tube 13 could also be a metal hypotube or a metal reinforcedplastic tube.

The conduits 20 would typically be made of a springy or shape memorymetal such as nitinol or a denser metal such as the cobalt chromiumalloy L605. It is also envisioned that to enhance radiopacity, theuninsulated distal ends 23 of the wires 24 could be plated in gold orother radiopaque material. Another way could be to have a gold capattached to the distal end needle tip 23 of the core wire 24. Theinsulated layers 22A, 22B and 22C are of a plastic material or anyinsulating coating. The guide tube 30 radiopaque marker 32 could be madeof a radiopaque material such as gold, platinum or tantalum or an alloyof these or similar metals. The core wire 42 of the fixed guide wire 40would typically be stainless steel and the outer layer 44 would bewrapped platinum or platinum iridium wire. The outer layer could also bea polymeric material. Any or certain portions of the outside of the NSC10 could be lubricity coated to provide improved performance. In typicalembodiments for renal nerve ablation, the conduits 20 should be smallerthan 0.5 mm in diameter and preferably less than 0.3 mm in diameter toavoid any blood loss or leakage as the conduits 20 penetrate into thewall of the target vessel and are then removed.

While a solid wire 24 is shown in FIG. 3, it is clear that a wire tubecould be used in its place that would allow fluid injection as well assensing or stimulation to occur from this embodiment. In an embodiment,if fluid is to be injected through the conduits 20 then the inside ofthe conduit lumen could be coated to provide electrical insulation anddeter or dampen any potential interaction between the fluid and theelectrical signal that are both transmitted along the wire tube.

FIG. 4 is the enlargement of section S4 of FIG. 2 showing the transitionfrom the central portion of the NSC 10 to the distal portion of the NSC10, including the outer tube 13, middle tube 12 and inner tube 11. Alsoshown is the connection between the outer tube 13 and the outer tubeextension 14.

The guide tube connector 18 connects the three guide tubes 30 to themiddle tube 12 that provides the impetus for advancement and retractionof the three guide tubes 30. The motion of the middle tube 12 isproduced by the motion of control mechanisms at the proximal end of theNSC 10. The plastic cylinder 17 lies inside of the distal portion of theinner tube 11 and connects together the three conduits 20 with corewires 24 and insulated layers 22A, 22B and 22C (not shown), so thatadvancement and retraction of the inner tube 11 provides simultaneousadvancement and retraction of the conduits 20. Also shown in FIG. 4 arethe flushing spaces between the several tubes. Specifically shown is theouter annular space 9 between the middle tube 12 and the outer tube 13and the inner annular space 19 between the inner tube 11 and the middletube 12. Each of these spaces 9 and 19 are to be flushed through withnormal saline solution prior to insertion of the NSC 10 into thepatient's body.

FIG. 4 also shows how the conduit 20 with insulating layer 22A extendsfrom the distal end of the plastic cylinder 17 inside the distal end ofthe inner tube 11 and then enters the lumen of the inner layer 38 of theguide tube 30 at the proximal end of the guide tube 30. The guide tubes30 and guide tube connector 18 are attached coaxially within the distalsection of the middle tube 12. Thus longitudinal motion of the middletube 12 will cause longitudinal motion of the guide tube connector 18and guide tubes 30 thus allowing the mechanism at the proximal sectionof the NSC 10 to advance and retract the guide tubes 30 with respect tothe outer tube 13 and outer tube extension 14.

The penetration depth limitation advantage of the catheter system 10could be realized in various manners. In one embodiment, this isaccomplished using a mechanism that limits the forward motion of thedistal end of the inner tube 11 with respect to the guide tube connector18. For example, a ring or other structure situated between the distalend of the inner tube 11 or plastic cylinder 17 and the proximal end ofthe guide tube connector 18 would limit the forward (towards distal endof the catheter) motion of the distal end of the inner tube 11 and thuslimit penetration of the conduits 20 beyond the distal ends 34 of theguide tubes 30. Such an extension limiting structure could beunattached, or attached to at least one internal structure of the NSC 10shown in FIG. 4 such as the inner tube 11, plastic cylinder 17, conduits20, guide tube connector 18, proximal ends of the guide tubes 30 or themiddle tube 12. Such an extension limiting structure could also have alength adjustment such as screw threads that would allow it to be usedby a user prior to, or after, insertion in a patient to adjust orcalibrate the penetration depth L1 of the conduits 20 beyond the distalends 34 of the guide tubes 30. The structure of the NSC 10 shown in FIG.4 is similar to that of FIG. 5 of Fischell et al U.S. Pat. No.8,740,849. While U.S. Pat. No. 8,740,849 shows transverse cross sectionsfor clarity they will not be shown here as they are nearly identicalexcept that in the illustrated embodiments the injector tubes with aplatinum core wire are now the conduits 20. As will be discussed, insome embodiments, the insulated conduits 20 may be realized as eithersolid wires or hollow wires which allow fluid to be provided at thedistal tips 23 such as to provide, for example, fluid-based ablation(when embodied as an PNASC), an ablative fluid, saline, or anestheticfluid as part of the procedure. Accordingly, in addition to the distaltips 23 serving as sensors, the conduits 20 may be configured to providefluid related to a sensing procedure.

FIGS. 8-11 of U.S. Pat. No. 8,740,849 also show a set of schematic viewsthat illustrate how the PTAC 100 disclosed therein is used forperivascular renal denervation. The same schematic views are applicablein embodiments of the NSC 10 of the current invention with conduits 20replacing the injector tubes with sharpened distal needles of the PTAC100.

FIG. 5 illustrates longitudinal cross-sections of the three portions ofthe central section of the NSC 10 of FIGS. 1 through 4 representing itsproximal, central and distal portions. At the proximal end of theproximal portion of the NSC 10 are three concentric metal hypotubes, anouter hypotube 82, middle hypotube 83 and inner hypotube 85. These aretypically made from thin walled metallic tubing such as stainless steel,L605, cobalt chromium or nitinol and provide the mechanical means formoving the distal guide tubes 30 and conduits 20 with respect to theouter tube extension 14. The outer hypotube 82 of the NSC 10 attaches atits distal end to a proximal portion of the plastic outer tube 92typically made from a relatively high durometer plastic, for examplepolyimide. As seen in the central portion of FIG. 5, the proximalplastic tube 92 attaches at its distal end to the proximal end of theouter tube 13 also shown in FIGS. 1 through 4. The outer tube 13 istypically made from a lower durometer/more flexible plastic than theproximal plastic tube 92. As shown in the proximal section of FIG. 5,the middle hypotube 83 is attached at its distal end to the middle tube12. As shown in the central section of FIG. 5 the inner hypotube 85 isattached at its distal end to the proximal end of the inner tube 11.Thus the NSC 10 from proximal to distal goes from relatively inflexiblemetal hypotubes 82, 83 and 85 to more flexible plastic tubes 13, 12 and11. This allows the distal section of the NSC 10 to be more easilyadvanced through a guiding catheter in the aorta whose distal end ispositioned near the ostium of a renal artery.

Also shown in distal section of FIG. 5 is the plastic cylinder 17 thatconnects the inner tube 11 to the conduits 20 as shown in FIG. 4. Theplastic cylinder 17 allows movement of the inner tube 85 that in turnmoves the tube 11 to move all three conduits 20 in the proximal anddistal directions

FIGS. 6 through 11 show an alternative embodiment of the NSC 100 whichis different than that shown in FIGS. 1, 2 and 3 in that the conduits120 are configured to be hollow while the conduits 20 of FIGS. 1-5 weredisclosed mainly as solid insulted wires. The conduits 120 include asensor tube 116. Inside the sensor tube 116 is an insulated wire 133 (ofFIG. 7) that connects to a distal electrode 117. The sensor tube 116 isin certain embodiments will be an electrode when it is connected to theelectrical equipment at the proximal end of the PNASC.

Like the NSC 10 of FIGS. 1-5, the embodiments of FIGS. 6-11 may be usedfor purely sensing nerve activity, non-ablative electrical stimulationof nerves and/or as a Perivascular Nerve Ablation and Sensing Catheter(PNASC). Ablation may occur using electrical (e.g. RF) or fluid ablationof nerves. The primary difference between the NSCs 10 and 100 is thatthe hollow metal sensor tubes 116 can act as a reference for theelectrode tip 117 allowing bipolar sensing and stimulation to occur ateach of the conduits 120.

FIG. 6 is a schematic view of the distal portion of a NSC 100 in itsopen position, showing an inner tube 105, middle tube 103, outer tube102, outer tube extension 104 having distal openings 131 through whichthe guide tubes 115 with radiopaque markers 122 are advanced outwardlyfrom the body of the NSC 100. Also shown is the tapered section 106 andfixed guide wire 110 with distal tip 109. The conduits 120 with centralwires 133 with insulation 134 of FIG. 7 and distal electrodes 117 carrythe signals sensed by the electrodes to an electronics module formonitoring and measuring the activity of the sympathetic nerves, orproviding current for electrical stimulation and/or nerve ablation.

The sensor tubes 116 with distal sharpened sensing needles 119 andsensing electrode 117 are shown in their fully deployed positions. Thesensor tubes 116 are ideally made from a memory metal such as NITINOL ora stiff springy material such as stainless steel or L605 a cobaltchromium alloy.

The openings 131 in the outer tube extension 104 support the sides ofthe guide tubes 115 as the guide tubes 115 are advanced outward againstthe wall of a vessel before the advancement of the conduits 120. The NSC100 of FIG. 6 has three guide tubes with the third tube hidden behindthe catheter and not visible in this schematic view. Although the NSC100 of FIG. 6 has three guide tubes 115, it is envisioned that otherembodiments could have as few as one or as many as eight guide tubeswith a typical number being three or four when provided for renal nerveablation. A larger diameter target vessel might suggest the use of asmany as 4 to 8 guide tubes 115 and sensor tubes 116. The primarystructure of the NSC 100 is based on the design of the PTAC 100 of FIG.2 of U.S. Pat. No. 8,740,849 except that the NSC 100 may be used tosense nerve activity instead of deliver ablative fluid into theperi-adventitial space. In the embodiment shown, the open position maybe approximately that which places the sensors in the periadventitialspace to allow measurement the activity, or used for energy or chemicalbased ablation of the sympathetic nerves outside of the renal artery.

Different shapes are envisioned for the distal openings (or windows) 131in the outer tube extension 104 where the guide tubes 115 exit. Thesepossible shapes include a racetrack design with curved (e.g., round)proximal and distal ends and straight sides in the axial direction, andoval or round shapes. It is also envisioned that there could be amovable flap covering the opening 131 or a slit that could be opened tomake the outer surface of the PTAC smooth for better delivery into therenal artery.

It is a feature of some embodiments of this invention that the guidetubes 115 act as needle guiding elements for the ultra-thin conduits120. Specifically, prior art such as Jacobson that has curved needlesthat are advanced outward without a guiding element from a centralcatheter to penetrate the wall of a target vessel. Without additionalguiding and backup support during advancement, needles that are thinenough to essentially eliminate the risk of extravascular bleedingfollowing penetration and withdrawal from the wall of the artery aregenerally too flimsy to reliably penetrate as desired into the vesselwall.

FIG. 7 is a longitudinal cross-section of a distal portion of the NSC100 as shown in FIG. 6. The proximal end of FIG. 7 shows the threeconcentric tubes, the outer tube 102, middle tube 103 and inner tube 105which form the central portion of the NSC 100. The outer tube 102 isattached to the outer tube extension 104 which is in turn attached tothe tapered section 106. The fixed guide wire 110 with core wire 111 andouter layer 113 extends distally from the distal end of the taperedsection 106. It should be noted that only part of the length of theguide wire 110 is shown in FIG. 7, its full length is shown in FIG. 6.Enlargements of the sections S8 and S11 of FIG. 7 are shown in FIGS. 8and 11 respectively. The conduits 120 have outer sensor tubes 116,distal needles 119 and distal sensor electrodes 117.

FIG. 7 shows the guide tube 115 with radiopaque marker 122 in its fullyadvanced position placed through the opening 131 in the outer tubeextension 104. The interior surface of the outer tube extension 104forms part of the tubular shaft 139 should be made from a stiff materialsuch as a metal or high durometer plastic so that it will be relativerigid as the guide tubes 115 are advanced and retracted.

While the inner tube 105, middle tube 103 and outer tube 102 couldextend proximally to the proximal handle 300 of FIG. 16, an alternativeembodiment of the central portion of the NSC is shown in detail in FIG.15.

The central buttress 121 shown in FIG. 7 supports the guide tube 115both as it is pushed distally, and after it is fully deployed. Thiscentral buttress 121 also provides radial support for the guide tubes115 after they are advanced against the interior wall of the targetvessel. This prevents the guide tubes 115 from backing away from theinterior wall of the target vessel as the conduits 120 are advancedthrough the guide tubes 115 penetrating the vessel wall then forward totheir desired position such as 2-6 mm beyond the interior surface of thewall of the target vessel. In some cases, the injection needles 119 atthe distal ends of the conduits 120 might be advanced as deep as, forexample, 10 mm beyond the interior surface of the target vessel.Additional lateral support for the guide tubes 115 is provided by thesides of the openings 131 that in combination with the central buttress121 provide radial and circumferential/lateral support both during guidetube 115 advancement and outward expansions, and as backup duringdelivery of the needles 119 through the interior wall of the targetvessel. The buttress may comprise a deflection surface such as a curvedor linear ramp, which may in a curved embodiment correspond to theradius of curvature of the distal surface of the guide tube 115.

Preferably the radius of curvature of the distal portion of the conduits120 have a central axis with the same, or nearly the same, radius ofcurvature as the central axis of the guide tubes 115 and of the centralaxis of the distal portion of the tubular shaft 139 that is formedwithin the central buttress 121 when measured in an unconstrained state.In addition, the length of the guide tubes 115 are preferably at leastas long as the distal curved portion of the conduits 120 with distalneedles 119. This would constrain the curved portion of each conduit 120within the lumen of the guide tube 115 so that the conduit 120 cannottwist or change position.

As seen in FIG. 7 the inner tube 105 attaches through the plasticmanifold 125 to the outer sensor tubes 116 of the conduits 120, thus thelumens of the sensor tubes 116 are in fluid communication with the lumenof the inner tube. This allows longitudinal movement of the inner tube105 to advance and retract the conduits 120 coaxially through the guidetubes 115. The inner tube 105 and manifold 125 can slide along thelongitudinal axis of the NSC 100 inside of the middle tube 103 which isshown with uniform diameter over its length including the portioncoaxially outside of the manifold 125.

It is clear from the drawing of FIG. 7 that the manifold 125 is locatedwithin the lumen of the inner tube 105 in a portion of the tube 105 thatis proximal to the distal end of the tube 105. The inner tube 105 andmanifold 125 are both located coaxially within the outer tube 102 of theNSC 100 at a position proximal to the outer tube extension 104 which isthe distal end section of the outer body of the NSC 100. This differssignificantly from the embodiment shown in FIG. 3 of the Jacobson U.S.Pat. No. 6,302,870 where the manifold that connects the tube to theneedles is attached to the distal end of the tube (instead of beinginside it and proximal to the distal end).

The insulated wires 130 including a core wire 133 and insulation 134, asshown in FIG. 8, connect the sensor electrodes 117 to the proximal endof the NSC 100 where they exit near the proximal end as shown in FIG.16. The wires 130 may there be connected to the external electronicslocated outside of the proximal end of the NSC 100. Different exampleconfigurations of the sensor electrodes 117 envisioned are shown inFIGS. 9, 10, 12, 13 and 14, which illustrate some preferred embodiments.

FIG. 8 is the enlargement of section S8 of the longitudinalcross-section of the NSC 100 as shown in FIG. 7. FIG. 8 shows thedetails of the guide tubes 115 with interior layer 123, outer layer 127,distal end 129 and radiopaque marker 122. Coaxially within the lumen ofthe guide tube 115 is the conduit 120 with sensor tube 116, distalsensing needle 119, sensor electrode 117 and insulted wire 130 with corewire 133 and insulation 134. Radiopacity of the distal end of the sensortubes 116 with distal needles 119 can in some embodiments be importantso that the operator can confirm under fluoroscopy that the needles 119have properly deployed into the wall of the target vessel. The presentembodiment uses the electrode 117 which would typically be formed from adense and highly conducting metal such as gold or platinum to providethis radiopacity. It is envisioned however, that other embodiments ofthe present disclosure may use coatings, plating or markers on theoutside and/or inside of the sensor tube 116 and needle 119 or thesensor tube 116 with distal needle 119 could be made from a two layerclad material.

The guide tubes 115 are advanced and retracted through the tubular shaft139 with distal opening 131. The three guide tubes 115 are attached toeach other near their proximal ends by the guide tube connector 132.FIG. 8 also clearly shows how the guide tube 115, when advanced againstthe central buttress 121 is forced outwardly and is supported by thecurved ramp 144 of the central buttress 121 as well as the sides of theopening 131 of the tubular shaft 139. The central buttress 121 also hasproximal fingers 142 that provide additional lateral support for theguide tubes 115.

The outer tube extension 104 connects at its distal end to the taperedsection 106 which in turn lies coaxially around the guide wire 110 (ofFIG. 6) with core wire 111 and outer layer 113.

Also shown in FIG. 8 is the penetration depth L2 which is the distancefrom the distal end 129 of the guide tube 115 to the distal tip of thesensor needle 119. Mechanisms at the proximal end of the NSC 100 (asshown in FIG. 16) control both the motion of the distal components suchas the sensor tubes 116 and guide tubes 115 as well as to limit and/oradjust the penetration depth L2 of the needles 119.

It is envisioned that the central buttress 121 and distal openings 131can, as shown in FIG. 8, be separate components of the NSC 100 or theycan be formed as a single molded or machined part. The distal tip 145 ofthe central buttress 121 provides the attachment to secure the buttress121 to the tapered section 106. Additionally, 121,131, and 106 could bea single molded or machined component.

While the preferred embodiment of the NSC 100 has the guide tubes 115with a pre-formed curved shape, flexible naturally straight guide tubesare also envisioned where the buttress 121 forces the straight guidetubes to curve outward against the interior wall of the target vessel.

The term “central buttress” as used herein includes the, ramp 144 orother deflection surface that provides radial and some lateral supportfor the deployed guide tubes 115. Specifically, the curved ramp 144 ofthe buttress 121 supports and guides the outward motion of the guidetubes 115 as they exit though the distal openings 131 and also provideradial support for the guide tubes 115 and injection tubes, as theyengage the interior wall of the target vessel. Additional lateralsupport is provided by the fingers 142 of the central buttress 121 aswell as the tubular shaft 139 and the sides of the opening 131. Aschematic view of such a central buttress is shown in FIG. 17 ofFischell et al U.S. Pat. No. 8,740,849.

While the central buttress shown in FIG. 8 is a plastic part, aradiopaque metal part, such as stainless steel, or a plastic materialthat includes radiopaque filler such as tungsten could be advantageouslyemployed for showing the exact location where the guide tubes 115 willexit the NSC 100. It is also envisioned that a radiopaque marker couldbe placed or attached to a portion of the openings 131 or buttress 121or outer tube extension 104 to show the likely spot where the guidetubes 115 and thus the needles 119 would engage the interior wall of thetarget vessel.

Many of the components of the NSC 100 are typically made from plasticmaterials such as polyamide, polyurethane, nylon or tecothane. Theseinclude the outer tube 102, middle tube 103 and inner tube 105, theouter tube extension 104, inner layer 127 and outer layer 123 of theguide tubes 115, the tapered section 106, the buttress 121, the guidetube connector 132 and the manifold 125. The manifold 125 can be amolded part or be epoxy or another resin that is injected to glue thesensor tubes together within the lumen of the inner tube 105.

It is also envisioned that any or all of the inner tube 105, middle tube103 or outer tube 102 could also be a metal hypotube or a metalreinforced plastic tube.

The sensor tubes 116 would typically be made of a springy or shapememory metal such as nitinol. The guide tube radiopaque marker 122 wouldbe made of a radiopaque material such as gold, platinum or tantalum oran alloy of these or similar metals. Any or certain portions of theoutside of the NSC 100 could be lubricity coated to provide improvedperformance. The sensor tubes 116 and needles 119 should typically besmaller than 0.5 mm in diameter and preferably less than 0.3 mm indiameter to avoid any blood loss or leakage as the needles penetrateinto the wall of the target vessel and are then removed.

FIG. 9 is a longitudinal cross section showing an enlargement of sectionS9 of FIG. 8 detailing the distal portion of the conduit 120 withsharpened needle 119 at the distal end of the sensor tube 116. Attachedinside of the distal portion of the sensor tube 116 is the electrode 117with insulation 139 that prevents the electrode 117 from coming intoelectrical contact with the metal sensor tube 116 in order to keep thetwo components from shorting out. The insulation 139 may also beconfigured to extent over the outside of the distal portion of thesensor tube 116 to reduce the potential for shorting further. Theconfiguration shown in FIG. 9 would allow the electrodes 117 to be usedfor sensing and/or stimulation as a dipole referenced to the sensor tube116 or a monopole referenced to another of the 3 conduits or a separatereference on another portion of the catheter or within the body or onthe skin of the patient. The insulated wire 130 with core wire 133 andinsulation 134 is attached to the electrode 117 as shown with a distalportion of the core wire 133 fixedly attached to the electrode 117. Thiscan be done using any of a number of mechanical or other techniquesincluding welding, brazing and crimping. Thus voltages sensed by theelectrode 117 will be transmitted by the conduits 120 to the proximalend of the NSC 100 where external equipment 500 of FIG. 21 can measureand analyze these signals to provide information relating to nerveactivity (e.g., sympathetic nerve activity), or the lack thereof, to theuser. When used either for ablation or to provide stimulation of thenerve that may be related to the sensing paradigm (e.g., assessingablation using evoked activity), then the external equipment may alsosend electrical signals to the core wire 133. In this embodiment with 3bipolar sensors, sensing evoked nerve activity can be accomplished byusing two electrodes on different conduits (or an electrode 117 andsensor tube 116) for stimulation and the other electrode 117 on thethird conduit for sensing (the sensing would typically occur after thestimulation is provided). In another embodiment, sensing, stimulation,or ablation can be provided using any of the electrodes 117 by selectingthe circuitry of the electronics 500 that is attached to thesensor/stimulator at the proximal site of the catheter system.

One technique for manufacturing the sensing tip configuration of FIG. 9is to adhesively attach a cylindrical electrode 117 with insulationinside the distal end of a cylindrical sensor tube 116. Allow theadhesive to fix and then cut or grind the distal end of the sensor tube116 with electrode 117 until the sharpened shape seen in FIG. 9 isproduced. Alternatively, one could assemble the parts already sharpenedas seen in FIG. 9.

It is also envisioned that the electrode 117 could be substituted by athermocouple or thermistor with the objective of using the NSC as atemperature sensor to know the periadventitial temperature during anenergy or cryo based ablation procedure. This temperature sensing couldbe used to guide the operation of a secondary device or could be used toguide operation of the PNASC itself. It is also envisioned that athermocouple or thermistor may be attached to the guide tubes 115 andcould be used for measuring the temperature of the intimal tissue usingthe external electronic equipment 500 to ensure that the temperaturefrom energy based ablation does not overheat the media and intima of theartery.

FIG. 10 is a transverse cross section of the distal portion of thesensor tube 116 at 10-10 of FIG. 9. Shown are the sensor tube 116, theinsulation 139, electrode 117 and core wire 133.

FIG. 11 is the enlargement of section S11 of FIG. 7 showing a preferredembodiment of the transition from the central portion to the distalportion of the NSC 100 including the outer tube 102, middle tube 103 andinner tube 105 with lumen 137. Also shown is the connection between theouter tube 102 and the outer tube extension 104. While the manifold 125in FIG. 11 shows the proximal end of the sensor tubes 116 at a positiondistal to the proximal end of the manifold 125, it may be preferable tomanufacture the NSC 100 with the proximal end of the sensor tube 116located at or proximal to the proximal end of the manifold 125.

The guide tube connector 132 connects the three guide tubes 115 to themiddle tube 103 that provides the impetus for advancement and retractionof the three guide tubes 115 of which two are visible in this view. Themotion of the middle tube 103 is produced by the motion of controlmechanisms at the proximal end of the NSC 100. The manifold 125 liesinside of the distal portion of the inner tube 105 and connects togetherthe three sensor tubes 116 so that advancement and retraction of theinner tube 105 provides simultaneous advancement and retraction of thesensor tubes 116. Also shown in FIG. 11 are the flushing spaces betweenthe several tubes. Specifically shown is the outer annular space 109between the middle tube 103 and the outer tube 102 and the inner annularspace 99 between the inner tube 105 and the middle tube 103. In typicaluse, each of these spaces 109 and 99 are to be flushed through withnormal saline solution prior to insertion of the NSC 100 into thepatient's body.

FIG. 11 also shows that the proximal end of the sensor tube 116 is influid communication with the lumen 137 of the inner tube 105. This canin some embodiments be important when the conduit distal portionincludes an opening for delivering an ablative fluid to the perivasculartissue for chemical tissue ablation such as shown in FIG. 13 for theembodiment of a Perivascular Nerve Ablation and Sensing Catheter (PNASC)200 with openings in the distal portion of a conduit.

The embodiment of the PNASC 100 of FIGS. 6 through 11 when connected toappropriate external equipment 500 of FIG. 21 can provide electricalstimulation and sensing and may also, be used for energy based tissueablation as a perivascular Nerve Ablation and Sensing Catheter (PNASC)when sufficient energy is delivered through the wires 130 and electrodes117.

Returning to FIG. 11, the wires 130 (for sensing/stimulation/ablation)with core wires 133 and outer insulation 134 run coaxially within thelumens of the sensor tubes 116 extend proximally from the proximal endof the sensor tube 116 within the lumen of the inner tube 105 all theway to the proximal end of the NSC 100 where they exit as the wires 361,362 and 363 and terminate in the connector 360 of FIG. 16 that allowsthe wires 130 to connect to external electronics 500 shown in FIG. 21for measurement of nerve activity and/or for providing stimulationsignals to achieve stimulation and/or ablation. Although in the exampleconfiguration that is shown there are three wires 130 each of whichterminate in a different electrode 117 of FIG. 9. In this configurationwith only three wires, the NSC would act as a monopolar device with eachelectrode referenced to another electrode or an independent referenceelectrode.

In other embodiments a single wire may conduct electricity to two ormore electrodes 117 which have an electrical bridging means incorporatedinto the catheter design in order to decrease the number of wires 130that are carried along the length of the catheter. In this alternativeembodiment, the same signal is provided to two or more electrodes 117 bya single wire 130.

It is also envisioned that a fourth reference wire could be added thatcan be bridged to the three sensor tubes 116 to act as the reference forthe bipolar electrodes 117. It is still further envisioned that separatereference wires could be run to each of the three sensor tubes with sixwires now running to the length of the catheter providing fullyindependent bipolar sensing from each of the three electrodes 117referenced to their own sensor tube 116.

Longitudinal motion of the inner tube 105 within the uniform diametermiddle tube 103 causes the manifold 125 and attached sensor tubes 116 toalso move longitudinally. This longitudinal motion caused by controlmechanisms near the proximal end of the NSC 100 will advance and retractthe sensor tubes 116 through the lumens of the guide tubes 115 to expandoutwardly to penetrate the inner wall of the target vessel to positionthe sensing/stimulation electrodes 117 of FIGS. 6 through 10 at adesirable perivascular location. For renal denervation applications,this would position the electrodes to sense activity as well asstimulate and/or electrically ablate the sympathetic nerves that lieoutside of the renal artery.

FIG. 11 also shows how the three sensor tubes 116 extend from the distalend of the inner tube 105 and manifold 125 and then enter the lumen ofthe inner layer 127 of the guide tube 115 at the proximal end of theguide tube 115. The guide tubes 115 and guide tube connector 132 areattached coaxially within the distal section of the middle tube 103.Thus longitudinal motion of the middle tube 103 will cause longitudinalmotion of the guide tube connector 132 and guide tubes 115 thus allowingthe mechanism at the proximal section of the NSC 100 to advance andretract the guide tubes 115 with respect to the outer tube 102 and outertube extension 104.

It is also envisioned that the penetration depth limitation could berealized by a limiting mechanism that limits the forward motion of thedistal end of the inner tube 105 with respect to the guide tubeconnector 132. For example, a ring or other structure situated betweenthe distal end of the inner tube 105 or manifold 125 and the proximalend of the guide tube connector 132 would limit the forward (distal)motion of the distal end of the inner tube 105 and thus limitpenetration of the needles 119 beyond the distal ends 129 of the guidetubes 115. Such a structure could be unattached, or attached to aninternal structure of the NSC 100 shown in FIG. 11 such as the innertube 105, manifold 125, sensor tubes 116, guide tube connector 132,proximal ends of the guide tubes or the middle tube 103. Such astructure could also have a length adjustment such as screw threads thatwould allow it to be used to calibrate the penetration depth of theneedles 119 beyond the distal ends 129 of the guide tubes 115.

FIG. 12 shows an alternative embodiment of the NSC 100 of FIGS. 7 and 8,labelled 100′, with the distal portion of a conduit 150. Except for theconduit 150, the remainder of the NAC 100′ is identical to the NSC 100of FIGS. 6, 7, 8 and 11. In this embodiment the electrode 154 withsharpened needle tip 159 is attached within the distal end of acylindrical sensor tube 152 with insulation 159 to prevent electricalcontact between the electrode 154 and the sensor tube 152. The distalend of the electrode 154 can be pre-sharpened or it could be sharpenedby cutting or grinding following attachment into the distal end of thesensor tube 152. This configuration has advantage over the tip of FIG. 9as it provides an electrode with significantly more surface area forsensing nerve activity voltage signals (and for providing stimulation orablation when the external electronics are configured to provide suchfunctionality). It also provides a greater distance between theelectrode 154 and sensor tube 152 for use as a bipolar electrode. Thesame wire 130 with core wire 133 and insulation 134 as shown in FIGS. 7through 11 is attached to the electrode 154.

FIG. 13 is an embodiment of the distal portion of the conduit 160 of thePNASC 200 integrated ablation and nerve sensing catheter. Except for theconduit 160, the remainder of the PNASC 200 is identical to the NSC 100of FIGS. 6, 7, 8 and 11. The tip 160 differs from the tip 150 of FIG. 12in that side holes 165A and 165B have been placed into the sides of thesensor tube 162 to allow ablative fluid injected at the proximal end ofthe PNASC 200 to flow through the lumen 137 of the inner tube 105 ofFIG. 11 into the lumens 167 of the sensor/injection tubes 162 and thenout of side holes 165A and 165B into the tissue of the media, adventitiaor periadventitial space depending on the depth of penetration of theneedles 169. In this embodiment, the electrode 164 with needle tip 169and insulation 159 are identical to that of the electrode 154 andinsulation 159 of the conduit 150 of FIG. 12. The sensor wire 130 isalso the same as in FIG. 12 with core wire 133 and insulation 134.

The conduits 120, 150 and 160 of the NSC 100 and PNASC 200 devices wouldpreferably be very small gauge (smaller than 25 gauge) to prevent bloodloss following penetration and removal through the vessel wall. Also thePNASC 200 which includes a distal opening in one or more of the conduits160 to provide egress for the ablative fluid, as shown in FIG. 13typically has a non-coring (cutting) needle 169. The PNASC 200 wouldalso preferably have at least 2 conduits 160 with distal electrodes 164,but 3 to 8 tubes with distal needles may be more appropriate, dependingon the diameter of the vessel to be treated and the ability of theinjected ablative fluid to spread within the perivascular space. Forexample, in a 5-7 mm diameter renal artery, 3 conduits 160 should beutilized if ethanol is the ablative fluid.

A PNASC 200 integrated ablation and sensing system may provide largeadvantages over other current technologies for applications in additionto renal denervation. For example, the PNASC 200 can provide a highlyefficient, and reproducible perivascular circumferential ablation of themuscle fibers and conductive tissue in the wall of the pulmonary veinsnear or at their ostium into the left atrium of the heart to treatatrial fibrillation (AF). Additionally, this system could benefitdenervation of the pulmonary arteries in the case of nerve ablation totreat pulmonary arterial hypertension. For the AF application, operatingthe catheter system to obtain nerve and/or cardiac myocyte electricalactivity measurements could be an effective technique to provideimmediate assessment of the success of an AF ablation procedure duringthe actual procedure. Other potential applications of this approach,such as pulmonary artery nerve ablation, or others, may also becomeevident from the various teachings of this patent specification.

The embodiments shown in FIGS. 12 and 13 could also be adapted todeliver ultrasonic energy to with an ultrasonic transducer replacing theelectrodes 154 and 164 with the voltage to activate the transducerprovided between the core wire 133 and the electrodes 154 and 164 andthe removal of the insulation layer 159.

FIG. 14 is another embodiment of the distal portion of the conduit 170of the PNASC 400 which can both inject ablative fluid and sense nerveactivity. Except for the distal portion of the conduit 170, theremainder of the PNASC 400 can be identical to the NSC 100 of FIGS. 6,7, 8 and 11. This embodiment uses a non-coring Huber type needleconfiguration with sharpened needle tip 189 with a turn in the distalend of the sensor/injector tube 172 to prevent coring duringpenetration. A radiopaque wire 171 with core wire 174 and insulation 178connects proximally to external equipment replacing the wires 130 ofFIGS. 7 through 11. The distal portion of the wire 171 has theinsulation removed to allow for the sensing of nerve voltages. To makethis work it is necessary to insulate the sensor wire 172 except for thedistal portion and also the proximal side where it connects to theexternal equipment shown in FIG. 21 and also insulate the inside of thedistal portion 170 of the PNASC 400 to prevent electrical shortingbetween the sensor/injection tube 172 and the core wire 174. The corewire 174 would typically be made from gold or platinum or an alloy ofgold or platinum. It is also envisioned that only the distal portion ofthe wire 171 would be radiopaque with the more proximal portion being astandard wire material such as copper.

FIG. 15 is a the longitudinal cross-sections of three portions of thecentral section of the catheter 450 that can be integrated into the NSC100, PNASC 200 and PNASC 400 of FIGS. 6 through 14. At the proximal endof the proximal portion of the catheter 450 are three concentric metalhypotubes, an outer hypotube 82, middle hypotube 83 and inner hypotube85. These are typically made from thin walled metallic tubing such asstainless steel, L605, cobalt chromium or nitinol. The outer hypotube 82attaches at its distal end to a proximal plastic outer tube 92 typicallymade from a relatively high durometer plastic, for example polyimide. Asseen in the central cross-section of FIG. 15, the proximal plastic tube92 attaches at its distal end to the proximal end of the outer tube 102also shown in FIGS. 6 through 8. The outer tube 102 is typically madefrom a lower durometer/more flexible plastic than the proximal plastictube 92.

As shown in the proximal section of FIG. 15, the middle hypotube 83 isattached at its distal end to the middle tube 103. As shown in thecentral section of FIG. 15 the inner hypotube 85 is attached at itsdistal end to the proximal end of the inner tube 105.

Also shown in distal section of FIG. 15 is the manifold 125 thatconnects the inner tube 105 to the sensor tube 116 as also shown in FIG.11. Thus the wires 130 with core wire 133 and insulation 134 exit theproximal end of the sensor tubes 116 and continue in the proximaldirection through the inner tube 105 and then proximally to that throughthe lumen 133 of the inner hypotube 85.

For the embodiment where the catheter 450 is utilized to inject a fluidinto the perivascular space, the lumen 138 of the inner hypotube 85 isin fluid communication with the lumen 137 of the inner tube 105 which isin fluid communication with the lumens of the sensor tubes 116 of FIGS.6-11, or the sensor tubes 152, 162 or 172 of FIGS. 12, 13 and 14respectively. The 162 and 172 being for the PNASC 200 and 400 whereinjection of an ablative fluid moves from the injection port 354 in thehandle 300 of the catheter and through the inner hypotube 85 into theinner tube 105 through the tubes 162 or 172 and into the perivascularspace through openings in the distal portions of the tubes 162 or 172.The inner hypotube 85 runs longitudinally to the fluid port or connectorat the proximal end of the catheter 450 to allow injection of fluids.

While it is envisioned that the outer tube 102, middle tube 103 andinner tube 105 could run all the way to the proximal end of the NSC 100or PNASC 200 or 400, the configuration of FIG. 15 is the preferredembodiment as it provides flexibility where needed near the distal endof the catheter with better control of the motion of the inner andmiddle tubes 105 and 103 as the metal hypotubes do not compress as theymove longitudinally while plastic may.

FIG. 16 is a schematic view of one embodiment of the proximal portion(handle) 300 of the NSC 10, NSC 100 or PNASC 200 or PNASC 400. The termsproximal portion 300 and handle 300 will be used interchangeably here.The handle 300 includes the mechanisms for advancing and retracting theneedle guiding elements/guide tubes 30/115 and sensor/injector tubes22/116 with distal needles 24/119 during the procedure to position theelectrodes 117, 154, 164 and 174 of the various embodiments of the NSC10, 100, PNASC 200 and PNASC 400 within the perivascular space.Similarly the handle 300 will do the same to position the distal tips ofthe conduits 20 of the SNASC 10 of FIGS. 1 through 5 and PNASC 200 ofFIG. 13 in the perivascular space. Such positioning allows for sensing,stimulation and energy based ablation of sympathetic nerve activity aswell as injection of ablative fluid for the PNASC 200 and 400embodiments of FIGS. 13 and 14.

The handle 300 also has locking mechanisms activated by first and secondcontrol mechanisms such as press-able buttons 332 and 342. Specifically,button 332 when depressed unlocks the motion of the guide tube controlcylinder 333 with respect to the outer tube control cylinder 335. Theouter tube cylinder 335 is attached to the outer hypotube 82 which is inturn connected to the tube 92 that connects to the outer tube 102 asseen in FIG. 15 or the outer tube 13 of FIG. 5. The transition section338 provides strain relief to avoid kinks at the connection between theouter tube control cylinder 335 and the outer hypotube 82.

The guide tube control cylinder 333 is attached to the middle hypotube83 that in as shown in FIGS. 5 and 15, connects to the middle tube 12 ofthe NSC 10 of FIGS. 1-4 or the middle tube 103 of FIGS. 6-8 that in turnis connected to the guide tubes 30 of FIGS. 1-4 or guide tubes 115 ofFIGS. 6 through 8. The guide tube control mechanism 330 allows the userof the NSC/PNASC to control the distal and proximal motion of the guidetubes 30 or 115 with respect to the outer tube 82 and includes thebutton 332 and the guide tube control cylinder 333. The needle controlmechanism 340 allows the user of the NSC/PNASC to control the distal andproximal motion of the conduits 20 of the NSC 100 of FIGS. 1-5 or theconduits 120 of the NSC 100 of FIGS. 6-8. The needle control mechanismincludes the button 342 and the needle control cylinder 345.

The button 342 when depressed, unlocks the motion of the needle controlcylinder 345 with respect to the guide tube control cylinder 333. Theneedle control cylinder is attached to the inner hypotube 85 of FIG. 15.Moving the needle control cylinder 343 with respect to the guide tubecontrol cylinder 333 will move the inner hypotube 85 which in turn willcause the relative longitudinal motion of the inner tube 105 of FIGS.6-8 with respect to the middle tube 103 of FIGS. 6 through 8 whichcauses the advancement and retraction of the sensor tubes 116 withdistal needles 119 though the guide tubes 115. This mechanism advancesand retracts the conduits 120 with distal electrodes 117 of FIGS. 6-10,as well as the electrodes 154, 164 and 174 of the distal tips shown inFIGS. 12, 13 and 14. Similarly this mechanism would advance and retractthe conduits 20 of FIGS. 1-5 by the controlling the relative motion ofthe inner tube 11 with respect to the middle tube 12.

The handle 300 shown in FIG. 16 has the flushing port 344. Port 344,which would typically have a Luer fitting, is shown with a cap 346. Port344 is used to flush with saline the annular spaces 139 and 59 as shownin FIG. 15 and in turn will flush the lumens 109 and 99 shown in FIGS.11 and 15. The injection port 354 which typically has an ablative fluidconnector fitting is shown with cap 356. For the PNASC 200 or 400embodiments, port 354 allows injection of ablative fluid into the lumen138 of the inner hypotube of FIG. 15 which then will flow into the innertube 105 and then into the sensor tubes 162 of the conduit 160 of thePNASC 200 of FIG. 13 and the sensor tube 172 of the conduit 170 of thePNASC 400 of FIG. 14. The tubes 162 and 172 have openings near or attheir distal end to allow flow of the ablative fluid into theperivascular space.

Although FIG. 16 shows one flushing port 344, it envisioned that two ormore flushing ports could be used to flush the internal spaces (otherthan the injection lumen) within the various embodiments of the NSC andPNASC. It is also envisioned that a single button and cylinder mechanismcould replace the two buttons 332 and 342. If this is the case, then atelescoping mechanism, internal to the proximal portion of the handle300 would, upon advancement of the single button, first advance theguide tubes 115 then advance the conduits 120 with distal electrodes117. Retraction of the single button would first retract the conduits120 and then retract the guide tubes 115.

While a standard Luer or Luer lock fitting could be used for theablative fluid connector fitting for the injection port 354, Fischell etal. in U.S. Pat. No. 8,740,849 describes a non-standard fitting thatwould be advantageous for injection of the ablative fluid. Because ofthe ablative/toxic nature of the ablative fluid, having a non-standardfitting for the port 354 would reduce the chance of accidentallyinjecting the ablative fluid into one of the other ports (e.g. 344) orinto the standard Luer fitting in the “Y” adapter typically used with arenal guiding catheter. It would also prevent the operator from thepotential error of injecting flushing solution or other agents containedin a conventional Luer lock syringe, through the lumen of the injectiontubes. It would also be an advantage for the non-standard fitting port354 to have a smaller lumen than a standard Luer fitting so as tominimize the catheter dead space/internal volume.

The handle 300 also includes a gap adjustment cylinder 348 that whenrotated in one direction reduces the penetration depth L1 of FIG. 3 orL2 shown in FIG. 8 which is the distance the needle tip 23 or needles119 extend beyond the distal ends 34 and 129 of the guide tubes 30 and115. Rotation in the other direction of the cylinder 348 will increasethe penetration depth L1 or L2. It is envisioned that the gap adjustmentcylinder 348 could be accessible to the user of the handle 300 withmarkings on the handle 300 to indicate the distance that will beachieved. This has advantages for use with the NSC 100 which is a purelydiagnostic catheter so that the depth of electrode placement can be setand then adjusted of more than one depth is desired. A handle that usesa gap to limit needle penetration depth is disclosed in U.S. Pat. Nos.8,740,849 and 9,056,185, which are incorporated by reference in theirentireties.

In another embodiment of the handle 300, the gap adjustment cylinder 348could be accessible only during assembly and testing of the handle 300at the factory. This fabrication method is designed to ensure a properlycalibrated penetration depth L1/L2 that is preset in the factory duringmanufacturing and testing of each NSC 10/100 or PNASC 200/400. Thisability to calibrate the penetration depth L1/L2 is useful to achievinga good yield during manufacturing. In other words, even with variationof a few millimeters in the relative lengths of the components of theNSC 10/100 or PNASC 200/400 such as the inner tube 105 and middle tube103 of the NSC 100, the distance L1/L2 can be dialed in exactly usingthe gap adjustment cylinder 348. In this preferred embodiment, the NSC10/100 or PNASC 200/400 would be labeled according to the penetrationdepth L1/L2. For example, the NSC 100 might be configured to have threedifferent depths L2 of 3 mm, 4 mm and 5 mm. It is also envisioned that aset screw or other mechanism (not shown) could be included to lock thegap adjustment cylinder 348 at the desired penetration depth settingafter calibration. While a gap adjustment cylinder 348 is shown here, itis envisioned that other mechanisms such as a sliding cylinder couldalso be used to adjust the depth L1/L2.

The wires 130 of FIGS. 6 through 13 and the wires 171 of FIG. 14 exitthrough the side of the most distal portion of the handle 300 as seen inFIG. 16. These three wires 130 (more wires could be used if moreelectrodes/needles are used, or one-to-many electrical bridging could beimplemented in the distal portion of the catheter in order to provideelectrical communication to these additional electrodes without the bulkthat would be associated with a larger set of individual wires) areconnected to an electrical connector 360 which in turns connects to theelectronics 500 of FIG. 21 where the voltages between pairs of wires 130can be measured, processed, and displayed as sensed data measurements.In the embodiment of the NSC 10 or 100, where there is no fluidinjection, the wires 130 may exit the proximal section of the handle 300through the lumen of the fitting 354 where the cap 356 has been removed.

A primary function of the handle 300 is to operate the NSC 10/100 formeasurement of the activity of the sympathetic nerves outside of therenal artery before, during and after a renal denervation procedure.With the integrated PNASC 200 or 400, the handle 300 also allows forinjection of an ablative fluid to be delivered to the perivascularspace. For example, the electrical signals communicated with the distalend of the catheter are transmitted along the wires 361, 362, and 363which exit the handle 300 to communicate with the external electronicequipment 500 that provides, for example, sensing. Additionally, thehypotubes communicate fluid from the injection port 344 toward thedistal tip.

FIG. 17 shows an alternative embodiment a longitudinal cross-section ofa distal portion of an Ultrasound Nerve Ablation catheter (UNAC) 600.The primary structure of the UNAC 600 is similar to that of the NSC 100of FIG. 7. The proximal end of FIG. 17 shows the three concentric tubes,the outer tube 602, middle tube 603 and inner tube 605 which form thecentral portion of the UNAC 600. The outer tube 602 is attached to theouter tube extension 604 which is in turn attached to the taperedsection 606. The fixed guide wire 610 with core wire 611 and outer layer613 extends distally from the distal end of the tapered section 606. Itshould be noted that only part of the length of the guide wire 610 isshown in FIG. 17, its full length is similar to that shown for the guidewire 110 of the NSC 100 in FIG. 6. Enlargements of the sections S18 andS19 of FIG. 17 are shown in FIGS. 18 and 19 respectively.

FIG. 17 shows the guide tube 615 with radiopaque marker 622 in its fullyadvanced position placed through the opening 631 in the outer tubeextension 604. The interior surface of the outer tube extension 604forms part of the tubular shaft 639 and can in some cases be made from astiff material such as a metal or high durometer plastic so that it willbe relatively rigid as the guide tubes 615 are advanced and retracted.

While the inner tube 605, middle tube 603 and outer tube 602 couldextend proximally to a handle such as the proximal handle 300 of FIG.16, the central portion of the UNAC can be constructed similar to thatshown in the embodiment of the central portion of the NSC 100 of FIG.15.

The UNAC 600 utilizes an ultrasound transducer 650 coupled by thecoupler 625 to three distal wires 616 with sharpened needle distal tips619. Thus, vibration from the transducer 650 is conducted to through thewires 616 into the perivascular tissue near the tips 619 of the wires616. With sufficient intensity the vibration will cause ablation of theperivascular tissue. Perivascular delivery of energy by ultrasound forrenal denervation can be advantageous in some cases over intravasculardelivery as the pain nerves are in the media of the renal artery and thenerves to be ablated are in the perivascular space.

The central buttress 621 shown in FIG. 17 supports the guide tube 615both as it is pushed distally, and after it is fully deployed. Thiscentral buttress 621 also provides radial support for the guide tubes615 after they are advanced against the interior wall of the targetvessel. This prevents the guide tubes 615 from backing away from theinterior wall of the target vessel as the needles 619 are advancedthrough the guide tubes 615 penetrating the vessel wall then forward totheir desired position 2-10 mm beyond the interior surface of the wallof the target vessel. Additional lateral support for the guide tubes 615is provided by the sides of the openings 631 that in combination withthe central buttress 621 provide radial and circumferential/lateralsupport both during guide tube 615 advancement and outward expansions,and as backup during delivery of the needles 619 through the interiorwall of the target vessel. The buttress may comprise a deflectionsurface such as a curved or linear ramp, which may in a curvedembodiment correspond to the radius of curvature of the distal surfaceof the guide tube 615.

Preferably the radius of curvature of the distal portion of the wires616 have a central axis with the same, or nearly the same, radius ofcurvature as the central axis of the guide tubes 615 and of the centralaxis of the distal portion of the tubular shaft 639 that is formedwithin the central buttress 621 when measured in an unconstrained state.In addition, the lengths of the guide tubes 615 are preferably at leastas long as the distal curved portion of the wires 616 with distalneedles 619. This would constrain the curved portion of each conduit 620within the lumen of the guide tube 615 so that the wires 616 cannottwist or change position.

As seen in FIG. 17 the inner tube 605 attaches to the ultrasoundtransducer 650 that connects through the coupler 625 to the wires 616.This allows longitudinal movement of the inner tube 605 to advance andretract the wires 616 coaxially through the guide tubes 615. The innertube 605, ultrasound transducer 650 and coupler 625 can slide along thelongitudinal axis of the NSC 600 inside of the middle tube 603. Twoinsulated wires 630 provide power for the ultrasound transducer 650 fromexternal equipment (not shown) beyond the proximal end of the UNAC 600.

FIG. 18 is the enlargement of section S18 of the longitudinalcross-section of the UNAC 600 as shown in FIG. 17. FIG. 18 shows thedetails of the ultrasound transducer 650 with connector pins 655 thatconnect through the wire connectors 635 to the inner conductors 633 ofthe wires 130. FIG. 18 also shows in detail how the inner tube 605attaches to the outside of the ultrasonic transducer 650 that isattached to the coupler 625 that transmits the ultrasonic energy to thewires 616. Also shown is the middle tube 603.

FIG. 19 is a longitudinal cross section showing an enlargement ofsection S19 of FIG. 17 of the UNAC 600. FIG. 19 shows the detail of thedistal portion of the guide tube 615 with distal end 639 and the wire616 with sharpened distal needle 619. The guide tube 615 has radiopaquemarker 622, outer layer 623 and inner layer 627. The radiopaque marker622 is a band made from a radiopaque metal such as gold, platinum ortantalum. The guide tube 615 is similar in construction to the guidetube 115 of FIGS. 7 and 8. The wire 616 should either be made from aradiopaque metal or its distal portion could be plated or coated with aradiopaque material. It is also envisioned that the wire 616 could be athin tube with a radiopaque wire through the center.

FIG. 20a shows an embodiment of a procedure to first assess theperivascular nerve activity prior to a renal denervation procedure, thenperform a renal denervation procedure followed by a post denervationassessment of nerve activity. For FIGS. 20a and 20b , the elementnumbers referenced in the 100s are shown in FIG. 8 and element number82, and those in the 300s, are shown in FIG. 16.

As show in FIG. 20a , the procedure using the NSC 100 of FIGS. 6-11would include the following steps although not every step is essentialand steps may be, excluded, simplified or modified as will beappreciated by those of skill in this art. The distal portion elementnumbers will reference the NSC 100 of FIGS. 6 through 11 although theyalso apply to the other similar embodiments shown of the NSC 10 (FIGS.1-5) and 100′ (FIG. 12) as well as the PNASC 200 and 400 of FIGS. 13 and14.

a1. The procedure begins by preparing the NSC 100 for insertion into ahuman body by flushing the device in step 270 which would typicallyinclude flushing all of the internal volumes of the NSC 100 with normalsaline or another fluid through the ports 344 and 354 of the handle 300of FIG. 16.

a2. Engage and position device within first renal artery in step 272which by inserting the distal end of the NSC 100 through a previouslyplaced guiding catheter with the guiding catheter distal end engagedinto the ostium of the renal artery where it attaches to the aorta andpositioning the distal portion of the NSC 100 as at the desired locationin the renal artery.

a3. Deploy sensors to target in step 274 which may include depressingthe button 332 (of FIG. 16), and while holding the outer tube controlcylinder 335 which is locked to the guide tube control cylinder 333,push the guide tube control cylinder 335 in the distal directionadvancing the guide tubes 115 until the distal end of the guide tubes129 come into contact with the inside wall of the renal artery limitingthe advance of the middle tube 103 of FIG. 8 and deploying the guidetubes 115 from inside the tubular shafts 120 and out through theopenings 31. The notch 331 will otherwise stop the distal motion of theguide tube control cylinder 333 when it engages the tube 344 at themaximum allowable diameter for the guide tubes 115.

Still in step 274, releasing the button 332 which relocks the relativemotion of the outer tube control cylinder 335 with respect to the guidetube control cylinder 333.

Still in step 274, depressing the button 342 that allows relative motionof the needle control cylinder 345 with respect to the guide tubecontrol cylinder 333 and while holding the outer tube control cylinder335 (which is now locked to the guide tube control cylinder 333) advancethe needle control cylinder 345 with distal end 349 until the internalgap 347 is closed against the proximal end of the gap adjustmentcylinder 348 inside the needle control cylinder 345 stopping the motionat the preset depth L2 for the needle tips 119 with respect to thedistal ends 129 of the guide tubes 115.

Still in step 274, releasing the button 342, which relocks the motion ofthe needle control cylinder 345 to the guide tube control cylinder 333.This places the NSC 100 in a configuration where the needles 119penetrate through the internal elastic lamina (IEL) of the renal arteryand penetrate to a preset distance (typically between 2 to 8 mm) beyondthe IEL into the perivascular space outside of the media of the renalartery.

a4. Configuring sensing components and obtaining sensed data in step 276which may include attaching the connector 360 to the external nerveactivity measurement equipment 500 of FIG. 21 and measuring theamplitude or level of sympathetic nerve activity between at least onepair of electrodes 117 of FIGS. 6-8.

Rather than measure the nerve activity between distal electrodes of theNSC 100, the nerve activity may be measured between individualelectrodes 117 and a separate reference electrode with a conducting wirethat is attached to the external equipment 500 of FIG. 21 and also tothe patient. Such a separate wire/electrode may be part of the NSCsystem. As another example, a wire connected to the catheter surface orfixed guide wire 110 of FIG. 6 may be attached to the externalelectronic equipment 500. The wire could communicate from the catheterbody to the electronic equipment by way of the connector 360 of FIG. 16.The separate reference wire with distal electrode could also be on theskin surface such as used for an electrocardiogram or percutaneouslyinserted into tissue within the patient. Finally, the separate referencecould be a wire attached to a skin surface electrode. The level of nerveactivity can be noted manually by the user and or might be saved inmemory of the external equipment 500.

a5. Retract the sensors/electrodes in step 278 which by depressing thebutton 342 and while holding the outer tube control cylinder 335,pulling the needle control cylinder 345 back in the proximal directionuntil the needles 119 are fully retracted back into the guide tubes 115.It is envisioned that a click or stop would occur when the needlecontrol cylinder 345 reaches the correct position so that the needles119 are fully retracted. Then releasing the button 342 locking themotion of the injection needle control cylinder 345 to the guide tubecontrol cylinder 333.

a6. Retract the guide tubes in step 279 by depressing the button 332releasing the relative motion of the outer tube control cylinder 335with respect to the guide tube control cylinder 333 and retracting theguide tubes 115 back into the tubular shafts 139 then releasing thebutton 332 locking the NSC 100 in its closed pre-deployment position.

a7. Retract the catheter system back in to the guiding catheter in step280 and then reposition the distal end of the guiding catheter into theostium of the second renal artery.

a8. Measure nerve activity outside of the second renal artery in step282 by repeating steps a1 through a7. The measurement of nerve activitycan include sensing at least one interval of nerve activity for aselected duration in order to obtain sensed data, processing the senseddata to obtain at least one baseline dataset which can include raw dataand/or at least one summary statistic. The measurement of nerve activitycan also include at least one of displaying and storing at least onebaseline value related to the baseline dataset. The summary statisticrelated to the baseline dataset can include values such as mean, median,and standard deviation of a measure; variance, peak amplitude, averageamplitude, peak frequency, average frequency, burst duration,guard-bands, and other measures as disclosed herein.

a9. In step 284 remove the entire NSC 100 and guiding catheter from thebody.

a10. Perform a renal denervation in step 286 on one (unilateral) or both(bilateral) arteries using energy based devices such as the Simplicity™catheter from Medtronic or the PTAC of Fischell et al U.S. Pat. No.8,740,849 and then remove the treatment device from the body.

a11. Assess the efficacy of the renal denervation in step 288, byreinserting the NSC 100 through the guiding catheter and repeat steps a2through a9. Using the difference in nerve activity between before andafter the renal denervation procedure, assess the effectiveness of therenal derivation for each artery. Alternatively, when steps 270 to 284are excluded, step 288 may simply entail measurement and assessment ofpost-ablation nerve activity such as comparing the sensed nerve activityto an appropriate population normative threshold value or otherwiseappropriate determined quantitative or qualitative treatment criterionto determine if the treatment criterion was met or failed to be met.

12. If the denervation was not sufficiently effective (treatmentcriterion was not met), repeat the denervation in step 286 by repeatingsteps a10 and a11 as needed until sufficient loss of sympathetic nerveactivity is seen.

a12. Finish the renal denervation procedure in step 290 by standardmethods at the end of a renal catheterization procedure.

In an alternative embodiment, the steps related to sensing nerveactivity outside of the first artery (either in steps 276 or 288) can bereplaced by steps which include stimulation of the nerves outside of thefirst artery as part of an assessment of the treatment in order todetermine if the ablative treatment met a treatment criterion. Forexample, a surgeon could measure the change in blood pressure resultingfrom the stimulation in order to determine if the nerves weresufficiently ablated (where no evoked change in blood pressure, or othertype of evoked response, might fail to be evoked when ablation wassuccessful).

In an alternative embodiment, steps 270 to 280 can be followed by steps286 to 290, whereby the first artery ablation therapy is assessed.Following successful treatment of the first artery the steps can berepeated for the second artery by performing steps 282 and 284 followedby steps 286 to 290, whereby the second artery ablation therapy occursand is then assessed.

Finally, if insufficient drop in blood pressure is seen at follow-upseveral days, weeks, or years after the initial ablation occurred, theNSC 100 can be used to assess sympathetic nerve activity as a follow updiagnostic tool. For example, the NSC 100 can be used to assess whethernerve activity is below a threshold level of activity. For example, thethreshold amount of activity can be defined based upon populationnormative criteria (with appropriate adjustment for gender, age, andmedication) or the activity recorded at the beginning or end of theearlier procedure carried out on the patient and this comparison candetermine whether repeat treatment is required.

Further, the NSC 100 can be used as a screening device to screencandidate ablation patients and assess whether they are suitable orunsuitable renal denervation candidates. The screening can occur beforea renal denervation procedure to assess sympathetic nerve activity of apatient to determine if the patient is a good candidate for renal nerveablation therapy. For example, the NSC 100 can be used to assess whethernerve activity is within some normal range (defined by looking at alookup-table that corresponds to ranges of activity that have been foundfor patients who are successfully treated with ablation therapy) thathas been found to indicate that ablation therapy may be successful.Additionally, the NSC 100 can be used as a screening device to screencandidate ablation locations. This may occur by obtaining a baseline ofsensed data and evaluating the sensed data in order to determine ifsufficient nerve activity is sensed at that location. For example, nervedensity may vary with respect to how far the catheter is positionedwithin the arterial vessel. For example, the nerve density/distributionmay vary as a function of the circumference of the artery, which tendsto get bigger as one moves proximally along the renal artery. Furtherthe target nerves may be clumped on one side of the artery rather thansurrounding it in a relatively balanced manner. If the baseline nervesensing at a first candidate ablation location does not recordsufficient activity then the NSC (after the distal needles areretracted) may be moved to a second candidate location, or rotated, andthen the activity can be sensed again. A comparison of the sensed dataat the first candidate ablation location can be compared to that in thesecond candidate ablation location, and the surgeon can then use theresult to determine the next step of the ablation procedure. The NSC 100may also be used to stimulate the sympathetic nerves outside of a renalartery and the evoked change, for example, a change in blood pressure orother cardiac-related measure can be an indication of the patient'ssuitability for a renal denervation procedure.

FIG. 20b , shows the steps associated with the procedure using the PNASC200 or 400 for the combination of renal denervation and subsequentassessment (e.g., via sympathetic nerve activity measurement with orwithout stimulation to time-lock a response from the patient) wouldinclude the following steps although not every step is essential andsteps may be simplified or modified as will be appreciated by those ofskill in this art:

a13. Flush the device to remove air from the lumens in step 470 whichmay include flushing the injection lumen with ablative fluid or ananesthetic such as lidocaine through the port 354 shown in FIG. 16leaving ablative or anesthetic fluid in the dead space within the PNASC200 or 400. Also flush all of the internal volumes of the PNASC 200 OR400 with normal saline through the ports 344.

a14. Engage and position the device within the first renal artery, inStep 472, which can include inserting the PNASC 200 OR 400 through apreviously placed guiding catheter, positioning the distal portion ofthe PNASC 200 OR 400 at the desired location in one patient's renalartery.

a15. Deploy the needles into/through the vascular wall in step 473,which can include depressing the button 332 shown in FIG. 16, and whileholding the outer tube control cylinder 335 which is locked to the guidetube control cylinder 333, push the guide tube control cylinder 335 inthe distal direction advancing the guide tubes 115 of FIG. 8 until thedistal end of the guide tubes 129 come into contact with the inside wallof the renal artery limiting the advance of the middle tube 103 of FIG.8 and deploying the guide tubes 115 from inside the tubular shafts 120and out through the openings 131. The notch 331 will otherwise stop thedistal motion of the guide tube control cylinder 333 when it engages thetube 344 at the maximum allowable diameter for the guide tubes 115.Release the button 332 which relocks the relative motion of the outertube control cylinder 335 with respect to the guide tube controlcylinder 333.

a16. Configure the sensing components and obtain sensed data in step474, which can include depressing the button 342 that allows relativemotion of the injection needle control cylinder 345 with respect to theguide tube control cylinder 333 and while holding the outer tube controlcylinder 335 (which is now locked to the guide tube control cylinder333) advance the needle control cylinder 345 with distal end 349 untilthe penetration limiting mechanism stops the motion and the preset depthL2 of the needles 169 or 189 with respect to the distal ends 129 of theguide tubes 115. There are two ways this can be done: 1) The distal end349 of the needle control cylinder 345 is pushed forward until itengages the guide tube flush port 344 or 2) the internal gap 347 isclosed against the proximal end of the gap adjustment cylinder 348inside the needle control cylinder 345

Release the button 342, which relocks the motion of the needle controlcylinder 345 to the guide tube control cylinder 333. This places thePNASC 200 or 400 in the configuration where the needles 169 or 189 withelectrodes 164 or 174 penetrate through the internal elastic lamina(IEL) and penetrate to a preset distance (typically between 2 to 6 mm)beyond the IEL into the perivascular space outside of the media of therenal artery. The depth of 2-6 mm will minimize intimal and medial renalartery injury. After the electrodes are in an acceptable position thenobtain sensed data and also process the data and display sensed datameasurements to a surgeon. The sensing can also be used to confirm theposition/depth of the needles in this step. For example, if the senseddata is too weak (e.g., the amplitude of the sensed nerve activity issmall) then the surgeon may increase or decrease the depth of theneedles in order to position these in an improved position for providingnerve ablation. Additionally, if the sensed nerve activity remains weakthen the surgeon may retract the needles and move the catheter moredistal or proximal or rotate the catheter before re-deploying theneedles. In this second position the sensed data can again be evaluatedin order to determine if the second candidate ablation location offersany advantage over the first. In this manner the surgeon can increasethe likelihood that the needles are in a location with nerve activity(and possibly a greater density or more appealing distribution ofnerves). This step 476 may therefore have a subcomponent set of stepsthat are related to selecting a promising ablation location/depth priorto carrying out the ablation to provide renal denervation.

Because the electrodes are situated outside of the media of the artery,nerves can be ablated without harming the media of the artery ascompared with intraluminal RF ablation where direct contact of theelectrode(s) with the intima can seriously damage the media.

a17. In step 476, attach the connector 360 to the external nerveactivity measurement equipment and measure the amplitude or level ofsympathetic nerve activity between at least one pair of electrodes 164of FIG. 13, or electrodes 174 of FIG. 14. Alternately, if a commonground wire is included in the PNASC 200 or 400 or provided by a skinsurface electrode then a measurement between a distal electrode and thecommon ground can be made. The level of nerve activity should be notedby the user and or might be saved in memory of the external equipment.

a18. Perform renal denervation in step 480, such as performing a renaldenervation procedure on the first artery using the PNASC 200 of 400. Ifit is a chemical renal denervation procedure then a syringe or manifoldwith syringes (not shown) can be attached to the port 354 of FIG. 16 andthe desired volume of ablative fluid is injected. The ablative agentwhich can be an ablative fluid, such as ethanol (ethyl alcohol),distilled water, hypertonic saline, hypotonic saline, phenol, glycerol,lidocaine, bupivacaine, tetracaine, benzocaine, guanethidine, botulinumtoxin, glycosides or other appropriate neurotoxic fluid. This couldinclude a combination of 2 or more neuroablative fluids or localanesthetic agents together or in sequence (local anesthetic first todiminish discomfort, followed by delivery of the ablative agent) and/orhigh temperature fluids (or steam), or extremely cold (cryoablative)fluid into the vessel wall and/or the volume just outside of the vessel.A typical injection would be 0.1 to 5 ml. This should produce amultiplicity of ablation zones (one for each injection needle 169 or189) that will intersect to form an ablative ring around thecircumference of the target vessel. The local anesthetic can be atinjected at the primary site of injection of ablative fluid, distal orproximal to the primary site. There may be some advantages of injectingan anesthetic proximal to the ablation site.

If an energy-based renal denervation procedure is to be used one maystill wish to inject a local anaesthetic first. Then the PNASC 200 or400 would be connected to an appropriate source of electrical energy andthe energy based renal denervation procedure would be performed using astimulation protocol that is designed to be sufficient to provide anapproximately circumferential ablation.

Use of proximal or distal anesthetic can also apply to prior art devicessuch as the PTAC of Fischell application Ser. No. 13/752,062. Contrastcould be added to the injection either during a test injection beforethe neuroablative agent or during the therapeutic injection to allowx-ray visualization of the ablation zone. With ethanol, as an ablativeagent, a volume of less than 0.6 ml is sufficient for this infusion asit will not only completely fill the needed volume including thesympathetic nerves, but is small enough that if accidentally dischargedinto the renal artery, would not harm the patient's kidneys. Ideally, avolume of 0.1 ml to 0.3 ml of ethanol should be used. The amount usedcould be the same for all renal arteries or it could vary depending onthe diameter of the renal artery into which the ethanol is to beinjected. The agrophobic, hygroscopic and lipophilic nature of ethanolenhances the spread allowing such a small volume to be effective. It isdesirable to fluoroscopically verify the deployment of the needles 169or 189 of FIGS. 13-14 into the vessel wall of the target vessel beforeinjecting the ablative agent or fluid.

A19. Asses the ablation treatment in step 482, such as after waiting upto 30 minutes for the ablative fluid to affect the nerves or the heatfrom the energy based denervation to dissipate, measuring the nerveactivity across at least one interval after the selected post-ablationduration has occurred and compare the post-ablation sensed activity to aselected value (prior baseline activity of the patient, populationnormative threshold value, etc. as has been disclosed) in order toassess the difference in nerve activity between before and after therenal denervation procedure. The difference can be assessed in relationto at least one treatment criterion in order to determine theeffectiveness of the renal derivation. Based upon the sensed datafailing to meet the treatment criterion (e.g., if insufficient decrementof nerve activity is seen) then repeat steps 8 and 9, and if theassessment meets the treatment criterion then the ablation was effectiveand move to step 484.

a20. Once sufficient nerve damage is determined, in step 484 thesensing/stimulation components (e.g., needles and guide tubes) areretracted into the device, such as by depressing the button 342 of FIG.16 and while holding the outer tube control cylinder 335, pull theneedle control cylinder 345 back in the proximal direction until theinjection needles 169 or 189 are fully retracted back into the guidetubes 115. Release the button 342 locking the motion of the injectionneedle control cylinder 345 to the guide tube control cylinder 333.

Then depress the button 332 releasing the relative motion of the outertube control cylinder 335 with respect to the guide tube controlcylinder 333 that is now locked to the injection needle control cylinder345. Retract in the proximal direction the guide tube control cylinder333 with respect to the outer tube control cylinder 335. This willretract the guide tubes 115 of the configuration of FIG. 9 back insidethe openings 131 in the outer body extension 104 the PNASC 200 OR 400.

In step 484 Retract the PNASC 200 OR 400 back into the guiding catheter140.

a21. If in step 485, both arteries have been treated, go to a21 and step490 to finish the procedure. Otherwise, in step 488, move the guidingcatheter 140 to the other renal artery and advance the PNASC 200 or 400into position. Repeat steps 473 through 484 for the other renal artery.

a21. In step 490, finish the ablation procedure such as by removing theguiding catheter with the PNASC 200 OR 400 from the body.

Fischell et al U.S. Pat. No. 8,740,849 discloses multiple techniques foruse of saline pre and intermediate flushing of the injection lumens ofthe PTAC 100 which can also be used here.

While the buttons 332 and 342, as described above, release the motion ofcontrol cylinders when depressed and lock when released, it is alsoenvisioned that they could also be interlocked as follows:

1. The first interlock allows the injection needle control cylinder 345to be unlocked only when the guide tube control cylinder 333 is in itsmost distal position where the outer tube 102 is pulled back and theguide tubes 115 are fully deployed.

2. The second interlock allows the guide tube control cylinder 333 to beunlocked only when the injection needle control cylinder 345 is in itsmost distal position where the needles 169 or 189 are retracted withinthe guide tubes 115.

These same interlocks can be applied to the NSC 10 or 100 of FIGS. 1-12.However, the interlocks can be advantageous in some embodiments whenassociated with the injection of a neurotoxic ablative fluid.

The combination of the buttons 332 and 342 with the control mechanismsdescribed above should make the use of the NSC 10 or 100 and the PNASC200 or 400 reasonably simple and straight forward. The operatorbasically presses button 332 and pushes the guide tube cylinder 333forward causing the guide tubes 30 or 115 to expand outward, thenpresses button 342 and advances the needles 23, 119, 169 or 189 forwardto penetrate the wall of the renal artery. Nerve activity measurementsand/or injections are performed then the reverse procedure is done withbutton 342 depressed and the needles 23, 119, 169 or 189 retracted, thenbutton 332 is depressed and the guide tube cylinder 333 is retracted inthe proximal direction retracting the guide tubes 30 or 115 within thebody of the catheter.

While a push-button activated handle where sections are pushed andpulled in the longitudinal direction to cause guide tube and needledeployment is shown in FIG. 16, it is envisioned that other techniquessuch as rotational mechanisms for locking or longitudinal motion canalso be used. The Fischell et al U.S. patent application Ser. No.13/643,070 filed Oct. 23, 2012, which is hereby incorporated byreference in its entirety, shows such a rotational locking mechanism inFIG. 33.

It should also be noted that in one variation of the procedure havingthe cap 356 locked onto to the fitting for the injection port 354 priorto placing the PNASC 300 or 400 into the patient's body will certainlyprevent any ablative solution from entering the renal artery duringinsertion of the PNASC 200 or 400 into the renal artery. Additionally,replacing that sealing cap 356 onto the fitting for the injection port354 as the PNASC 200 or 400 is moved from one renal artery to theopposite renal artery will also prevent any ablative solution fromentering the second renal artery. The cap 356 would also be locked ontothe fitting for the injection port 354 as the PNASC 200 or 400 isremoved from the patient's body. During the renal denervation procedure,the cap 356 would be removed only to inject ablative solution into theperivascular space of the treated vessel.

A stopcock attached to the port 354 could also be used such that whenclosed, it would prevent leakage of ablative fluid out of the needledistal openings of the PNASC 200 or 400. In reality of course, if therewere no cap 356 attached as the PNASC 200 or 400 is moved within thearterial system of the body, the blood pressure within the arterialsystem would if anything force any fluid within the injection lumens ofthe PNASC 200 or 400 back out of port 354.

The NSC 100 and the PNASC 200 or 400 can be packaged with the guidetubes 30 or 115 and the sensor tube 20, 116, 152, 162 or 172 fullyextended. The reason for this is that the preferred embodiment of theguide tubes are made from plastic such as polyimide formed into a curveshape. Such a plastic material may lose its shape over extended periodsof time if it were packaged retracted back into the tubular shaft 21 or120 which would straighten it. In this case, the device would be shippedin a protective packaging to ensure handlers do not receive needlesticks.

It is also possible to ship the device with the needles 23, 119 159, 169or 189 retracted within the guide tubes 30 or 115 for safety. The guidetubes could be coated with a brightly colored dye or formed from amaterial that is brightly colored in order to serve as a visualdeterrent when the needles are in their deployed position.

While this specification has focused on use of the NSC 100 and the PNASC200 or 400 for use in the measurement of nerve activity outside of therenal artery, it is also clearly envisioned that the apparatus andmethods of FIGS. 1-16 inclusive can be applied to measure electricalactivity outside of any vessel or duct of the human body and in the caseof the PNASC 200 or 400, inject any fluid for any purpose including thatof local drug delivery into a specified portion of a blood vessel or thevolume of tissue just outside of a blood vessel, or into prostatictissue via the prostatic urethra. For example these devices could beused to assess electrical activity in the wall of the left atriumoutside of the Pulmonary vein, and ablate the tissue there to diagnoseand treat atrial fibrillation. It could also be used to assess nerveactivity around a pulmonary artery, to assist in the treatment ofpulmonary hypertension.

While the embodiments shown in FIGS. 1 through 16 show three distalelectrodes, the presently disclosed structure can also be applied todesigns with one needle, two needles or 4 or more needles.

FIG. 21 is a block diagram of the external electronics equipment 500with power supply 522. The wires 361, 362 and 363 that exit the handle300 of the NSC/PNASC of FIG. 16 terminate in the connector 360. Theconnector 360 connects to the connector 560 of the electronics 500providing electrical conductivity from the NSC/PNASC wires 361, 362 and363 to the wires 561, 562 and 563 respectively of the electronics 500

The wires 561, 562 and 563 connect to each of the amplifiers (each ofwhich may have high, low, notch filters, and/or band pass filters) ofthe 3 A-D converters 521, 522, 523. The amplifiers can be referenced toa common ground 511, 512 and 513 respectively. Alternatively, althoughnot shown here, the amplifiers can be differential. For example, wires561 and 562 can be routed to differential inputs of a first amplifier(in one embodiment 563 can serve as ground or a separate wire attachedto the subject can serve as com/ground). In other embodiments, 562 and563 can be routed to the second amplifier, and 561 and 563 to the thirdamplifier. In this manner it is possible to provide 3 differentialamplified signals. Further, a multiplexor may be used to route thedifferent signals to different amplifiers. The routing can occur in auser selected manner (e.g. by adjusting a controller that determines theelectrode montage, or can be controlled according to a sensing protocolimplemented by the processor 540. In addition to the amplification shownin the figure further amplification modules may be incorporated into thecircuitry such as isolated amplifiers, and pre-amplifiers).

The amplified signals from the amplifiers 511, 512 and 513 are convertedto digital signals by the analog to digital converters 521, 522 and 523respectively. The digital signals from the analog to digital converters521, 522 and 523 are stored in the circular First-In-First-Out Buffers531, 532 and 533 respectively that are read by the Central ProcessingUnit (CPU) 540 with RAM 542 and program memory 545.

In one embodiment the amplification and signal processing can beachieved using commercially available bioamplifiers and data acquisitionsystems (e.g. a Model 15LT Bipolar Portable Physiodata Amplifier Systemoperating in conjunction with a national instruments NI USB-6212 BNCmultifunction data acquisition unit or AD Instruments Bio Amps operatingwith a Powerlab system for recording extracellular potentials) whichfeed into a computer that is operating as part of the electronicsequipment. The CPU is connected to a Visual display 520 and a sonictransducer or loudspeaker 547 and receives input from a button touchpad550 or touch sensitive screen of the visual display. The visual display520 may be as simple as a set of LEDs or it can be a full graphicdisplay such as an LCD screen of a laptop, tablet or smartphone. Thebutton touchpad can be a limited or custom set of buttons or a fullnumeric or alphanumeric (e.g. QWERTY) keyboard for obtaining user input.

A clock/timing circuit 549 provides timing for the electronics 500including the analog to digital converters 521, 522 and 523, the FIFObuffers 531, 532 and 533 and the central processing unit (CPU) 540. Theelectronics 500 can be connected to a computer(s), equipment,accessories and electronic systems through the wired Input/Output (I/O)port 570, for example an RS-232 serial port or USB 1, 2, or 3 type port.The wired Input/Output (I/O) port 570 can also be used to obtain inputfrom an amplifier that senses patient data from one or more electrodesor other sensor located outside of the patient (e.g., ECG or bloodpressure meter). A wireless I/O sub-system 575 is also connected to theCPU 540 allowing wireless communication to and from other electronics,computer systems, and wireless local area network of a hospital, forexample a Bluetooth or Wi-Fi protocol wireless circuit may be used.

The RAM 542 includes the storage for baseline data 544 and “current”nerve activity sensed data 546 that are captured at points during theablation procedure. The data can include raw waveforms summary, andtrend data. The RAM 542 can also contain as well as program protocols(for providing stimulation, sensing, or ablation), parameter values,criterion used during the treatment, and other values for settings thatare used during screening, processing sensed data, and assessment ofsensed data as can occur for the detection of significant changes innerve activity indicative of effective denervation. The values of theRAM can be accessed by the stimulation subsystem 580 or the sensingsubsystem which is realized, at least in part, by the combination ofamplifiers, A-to-D converters, FIFO buffers, and CPU.

A Hard Disk (HD) or Solid State Disk (SSD) provides non-volatile datastorage for the electronics 500 including recorded nerve activity andpre-set programs for operation.

A stimulation sub-system 580 contains signal generators related toproviding stimulation and/or ablation signals and is controlled by theCPU 540. The stimulation sub-system 580 is connected to the wires 561,562 and 563 that are in turn connected through the connectors 560 and360 to the wires 361, 362 and 363. The connections of wires from thestimulation sub-system to the wires 561,562,563 can include multiplexorcircuitry and other electronics in order to isolate and/or protect theamplifiers 511,512,513 during the provision of stimulation and/orablation. This allows the stimulation sub-system to provide electricalenergy for energy based ablation. In one configuration, the stimulationsub-system 580 would deliver the electrical energy sequentially to pairsof wires. In another embodiment, the sub-system 580 would deliver energybetween any individual pair of the three electrodes 117 of FIG. 7, twoof the three electrodes to the third as a reference return electrode orany combination of the three electrodes to a common reference returnelectrode either using a skin surface electrode or a portion of thecatheter such as the guide wire 110.

The electrical energy delivered to a patient may take different forms.In a preferred configuration, the stimulation sub-system 580 maygenerate RF energy as is now used by devices such as the MedtronicSimplicity device. For the PNASC 600 embodiment of FIG. 17 withultrasound energy delivery, the stimulation sub-system 580 would providethe electrical energy to drive the ultrasound transducer 650.

The wired I/O port 570 and/or wireless I/O port 575 may allow foranother stimulator (not shown) to be used under control of the CPU 540with the electronics 500 used for sensing only. The ports 570 and 575also can be used to control an external pump that may be furtherconfigured to heat or cool a liquid such as saline, so that atemperature controlled liquid can be provided to the proximal section ofthe PNASC 200/400 of FIG. 13 or 14 for chemical or heated or cooledfluid delivery for renal denervation.

Additionally, rather than stimulators, the ports 570 and 575 can beconnected to systems of sensors to record data related to, for example,ECG, heart rate, or blood pressure. This may be essential as time-lockednerve activity measurement may require synchronization with theheartbeat.

The electronics 500 would typically connect to the wires 361, 362 and363 connected to distal PNASC electrodes for both stimulation andsensing at different moments in time. It is also envisioned thatstimulation and sensing could occur simultaneously. For example, usingwire 561 as a common, stimulation could be provided to wire 562 withsensing from wire 563. This would typically be a stimulation signalfollowed by sensing although it is envisioned that simultaneousstimulation and sensing would be possible.

FIG. 22 shows the modules 504 through 524 that may be included in theprogram memory 545 of the electronics 500.

The modules contain software, electronics, and/or firmware, foraccomplishing the functions disclosed. Modules can share resources andbe controlled by other modules or components. The electronics system 500includes a control module 502 for controlling the overall function ofthe electronics 500. The stimulation module 504 provides control of thestimulation sub-system 580 for providing electrical stimulation and/orenergy based ablation through the electrodes such as the electrodes 117of FIG. 7 that are positioned beyond the interior wall of the renalartery for the renal denervation application. The stimulation module 504control of the stimulation sub-system 580 of FIG. 21 controls thegeneration of stimulation signals which can include RF signals, pulses,or arbitrary waveforms for output including alternating current (AC)and/or direct current (DC) signals to be used by electrical, stored inthe protocols and parameters module 506. Treatment protocols that arestored in the protocols magnetic, optical, sonic, ultrasonic or othertypes of stimulators that are provided within catheter device with whichit is configured to operate.

The sensing and assessment module 505 (which may also be termed asensing subsystem) provides control for the measurement of nerveactivity collected by the CPU 540 from signals coming through theamplifiers 511, 512 and 513, A to D converters 521, 522 and 523 (whichcan include analog or digital filtering, processing, additionalamplification, isolation, and safety circuitry) and FIFO Buffers 531,532and 533. The sensing and assessment module 505 controls the comparisonof current nerve activity stored in the RAM 542 (e.g., in the RAMportion 546) with reference values or data such as previously recordedbaseline nerve activity (e.g., stored in RAM location 544). The module505 can determine if one or more selected treatment criteria have beenmet or not and therefore determine whether one of effective nerveablation or ineffective nerve ablation has occurred. The Control module502 can operate both stimulation module 504 and sensing module 505according to treatment protocols and parameters and parameters module506 can include nerve stimulation protocols, sensing protocols, ablationprotocols, and evaluation protocols that enable the electronics system500 to allow a medical practitioner to responsively adjust the cathetersystem operation in relation to the evaluation of sensed data, doctorinput, time intervals, detection of events, and other triggers that cancause the selection, provision, and adjustment of therapy. In oneembodiment, the control module can operate in a semi-automatic or fullyautomatic closed-loop manner to adjust the ablation treatment providedbased upon the assessment of sensed data.

The sensing and assessment module 505 can also be used to calculatevarious quantitative measurements that can be derived from sensed data.The assessment of sensed data may also include allowing a user toretrieve and display at least one of raw, summary, and trend results ofsensed data for a patient that were collected at different moments intime. Assessment of data and modification of the ablation treatment mayoccur in a closed loop manner in which the stimulation is adjusted inrelation to an evaluation of sensed data. Additionally or alternativelysuch assessment may cause information (information about the senseddata) or status signals displayed on the visual display 52 of FIG. 21 tobe presented to a user of the electronics system 500. Sensing circuitryand sensors can be configured to allow the catheter system to measuresuch aspects as temperature. For example, at least one thermocouple orother temperature sensor for measuring the temperature of the monitoredtissue or of the RF energy delivery element can be provided at thedistal tip of the catheter. The catheter system can be configured toacquire temperature or impedance measurements inside of, along, within,or outside of the wall of the vessel that is in the vicinity of thetreatment target area.

Nerve stimulation can include stimulation that is provided, for example,in order to assess evoked cardiac activity or evoked activity of thesympathetic nerve that is triggered by stimulation or may includeelectrical nerve ablation such as RF ablation or electrocautery. Thestimulation protocol can determine which of one or more stimulators orsensors on the catheter are used for stimulating, ablation, and sensing.The electronics system 500 can also simply provide stimulation,ablation, or sensing under the manual control of a doctor. The controlmodule 502 has access to the clock/timing sub-system 549 including areal time clock and a timer.

The protocols module 506 can include, for example, a subroutine forprocessing data as part of steps such as step 288 of FIG. 20a . Forexample, sensed data can be evaluated according to at least onetreatment criterion, and if the criterion is passed then the ablationprocedure is finalized, and if the treatment criterion is not passed,then ablative stimulation is adjusted, repeated, or otherwise provided,as defined by the treatment protocol as per step 286 of FIG. 20 a.

In one embodiment a characteristic of the sensed data is evaluatedbefore and after treatment in order to determine if a reduction in thecharacteristic has occurred due to therapy. In one embodiment thecharacteristic is the peak (or mean) amplitude or frequency of energywithin at least one selected frequency range, and reflects the energywithin a selected frequency band. The energy may be assessed byproviding at least one band-pass, low-pass, or high-pass filterimplemented with digital signal processing and allows the CPU 540 ofFIG. 21 to filter the sensed data prior to its measurement of nerveactivity. A ratio may be calculated related to energy in a firstfrequency range (spectral band) compared to energy in a second band.

In another embodiment, the CPU 540 can perform spectral analysis on thedata to derive frequency, time-frequency, or time-locked time-frequencyresults. In yet another embodiment, a signal characteristic can bemeasured for 2 or more electrodes and can assess inter-electrodecoupling. For example, prior to ablation the sensed data sensed from 2or more electrodes may be more largely correlated due to the nervesignals being transmitted along the renal artery. After successfulablation a decrease in the post-ablation correlation or coherence (forone or more frequency ranges) should decrease relative to the baselinecorrelation or coherence. Successful ablation can be defined to haveoccurred when at least one characteristic of the sensed activity relatedto an absolute activity level, a relative activity level (e.g., comparedto baseline), or activity differences between 2 or more electrodes (e.g.decrease in coherence or correlation) meets at least one definedtreatment criterion. The one or more characteristics of the sensed datacan be displayed by the visual display 520 to the user, and a history ofvalues for the characteristic(s) can be stored by the CPU 540 in the RAM542 or permanently in the SSD/HD 590.

There are numerous scientific articles describing methods of measurementof nerve activity but for this application, the display 520 may show adigital display of one or more electrical characteristics such as thepeak voltage, average voltage, peak power and/or average power of sensednerve activity. The difference (or ratio) in measurements before andafter the renal denervation procedure can be used to assess theeffectiveness of the procedure. Of these average voltage would be apreferred measurement.

The display 520 could provide a graphical display of the actual sensedsignals as well as means to select which pair of electrodes is beingused to derive a bipolar signal that is displayed. For example, usingthe button touchpad 550, control can be provided to enable a user tochoose electrodes pair derivations such as 1-2, 2-3 or 3-1 would bedesirable. This would have electrode 1 corresponding to wire 561,electrode 2 to wire 562 and electrode 3 to wire 563.

Monopolar derivations where electrode 1 is referenced to an electrodelocated distally within a patient could also allow electrical activityto be localized to a more specific degree since the active electroderecording the activity would reflect nerve activity and the referenceelectrode would not.

A calibration module 509 allows a user in to normalize the signal levelduring initial measurement of sympathetic nerve activity and capture thebaseline nerve activity signal and thus establish the baseline activitylevel stored in the RAM portion 544 of FIG. 21.

In one embodiment, the visual display 520 would include 5 LEDs thatcould be activated to show maximum activity at the time ofcalibration/baseline recording. Following the renal denervationprocedure, the user could operate the electronics module to cause apost-therapy measurement to be obtained. The reduction in nerve activitybetween the pre-therapy measurement and the post-therapy measurementwould be displayed by illumination of the new level compared to thenormalized value.

For example, if the post denervation level is 40% of the normalizedlevel for one of the sensors, then only 2 of the 5 LEDs would be litshowing a 60% drop in nerve activity. An example of even simpler versionwould have the visual display 520 include a green, yellow and red LEDfor various sensors. wherein this example, green indicates normal nerveactivity, yellow indicates a partial reduction and red indicates asignificant reduction. A more complex embodiment could use the baselineas a “control” level of activity and then calculate the average activityover a specified measurement time interval. The measurement protocolstored in the module 506 could then be configured to compare the sensedactivity over a similar duration of nerve activity measurement whichoccurs after ablation therapy. The visual display 520 using analphanumeric of full graphical display can be configured to display aquantitative, numerical reduction value (e.g., “Nerve activity reducedby 64% compared to baseline nerve activity.”)

A sensed data characteristic can be related to a measured neurogram. Aneurogram may be obtained by analog means by sending the sensed neuralactivity through a band pass filter (e.g., band-width, 700-2,000 Hz) andthen a resistance—capacitance integrating network (e.g., time constant,0.1 second) to obtain a mean voltage waveform. A digital signalprocessing equivalent to this can also be performed by the CPU 540according to a digital signal processing protocol stored in the module506. The neurogram may be processed to represent the average envelope ofthe response in order to measure amplitude, burst rate, and othermeasures as is well known.

In addition to ongoing activity, the sensed data can reflect evokedactivity recorded in response to an evoking stimulus such as electricalor pharmaceutical stimulation, or other evoking stimulus.

The sensed data can also be evoked by a change in the patient's state.For example, the patient state can be adjusted by raising and loweringblood pressure as can occur by providing vasoactive drugs to thepatient. Either the baseline or post-ablation activity, or both, may betaken with blood pressure being higher or lower than might otherwiseoccur in the patient, in the absence of such intervention.

In an embodiment, re and post assessment of patients can be adjustedbased upon patient characteristics. For example, patients can be dividedinto two groups based upon high or low basal microvolt levels of renalsympathetic nerve activity. Assessment for the two groups may then occurdifferently. For example, patients with high basal microvolt levels ofactivity may have their baseline taken without intervention, while a lowbasal microvolt level patient may be assessed after drug exposure toincrease activity during at least one of the baseline or post-ablationperiod.

One measure of neural activity that may be assessed, is peak burstheight (or maximum voltage) which can reflect the number of activefibers in renal sympathetic nerve activity (RSNA) or synchronized RSNA.This measure may reflect residual nerve activity better than anypost-ablation changes in average rhythm/burst rate/frequency over time,or peak frequency of the nerve activity. Nonetheless both amplitude andfrequency of the activity (e.g., bursts) may be used to assesspost-ablation nerve activity change relative to the pre-ablationbaseline or relative to a threshold which defines successful therapy.Peak duration is influenced by the firing synchrony and the dispersionof the mass discharge due to different conduction velocities of themultiple renal nerve fibers. Peak duration, or averaged peak duration,may also be used to assess post-ablation changes in nerve activity.

Other measures can also include: average voltage; bursts/min; averageburst count; average burst amplitude; assessment of cyclical signatures;integrated and/or rectified renal sympathetic nerve activity (SNA);“leaky” or resetting integrators to integrate over time or up to adefined threshold; amplitude at a spectral frequency range associatedwith nerve activity; and, time locked activity recorded in response toan evoking stimulus such as at least one a drug or external electricalstimulus or internal electrical stimulus such as the ECG signal ornon-electrical stimulus such as oscillation of arterial pressure. Ofcourse any of these measures can be normalized to baseline.

Correlation measures of recorded sensed data can also be obtained.Correlation may be accomplished between two electrodes and may befurther processed according to cardiac data sensed by sensors locatedexternal to the patient. For example, correlation may also be calculatedto assess association between heart beats, heart rates, and burstingpatterns.

The SSD/HD 520 of FIG. 21 may be configured to store a historical recordin order to summarize, track, and store the ablation treatment that wasprovided and sensed data that was obtained which may be especiallyhelpful evaluating what occurred during therapy.

The input/output module 507 works in conjunction with the control module520 for presenting information to a user (e.g. physician) through thevisual display 520 and/or sonic transducer 547 of FIG. 21 and obtaininginformation/input from the user through the touchpad 550 or touchsensitive display, when provided. In addition to data, the visual andsonic transducers can present the user with alarms or notificationrelated to the provision of therapy (e.g., a timer can be shown on thescreen or an audio-sound can be related to a measurement of sensedactivity, such as presenting a pitch that varies with the amount ofsensed nerve activity). While not shown in FIG. 21, although theelectronics system 500 may communicate in a wired or wireless mannerwith, or be realized within, a specialized device, smartphone, laptop,or tablet computer the specialized device containing a visual displayand loudspeaker. The device 500 can also contain user interface module524 which interacts with user controls 525 such as nobs, switches, etc.to allow a user to provide input, such as through a menu guided system,as well as adjust operation of the device by manually adjusting nobsrelated to the operation of the device.

Both the control module 502 and the waveform generator module 512 may beconfigured with safety hardware and software routines, includingcalibration routines to calibrate the apparatus 500 and to ensure properfunctioning.

The modules and components described for the apparatus 500 of FIGS. 21and 22 are for illustration purposes only and the device used by thesystem of embodiments of the present invention can be realized with lessthan or more than the modules and system components described herein.

It is also envisioned that rather than conducting wires, that opticalfibers may be used for signal conduction through the catheter and fordelivery of laser based ablation for the nerve fibers It is alsoenvisioned that a solid state laser instead of an electrode could belocated at the distal portion of the catheter to turn electrical energyinto light for ablation. Such a laser could also be located in place ofthe ultrasonic transducer 650 of FIGS. 17 and 18 that could then sendoptical signals for ablation through optical fibers that would replacethe wires 616.

It is also envisioned that the sensing capabilities of the NSC and PNASCpresented here may have, in some embodiments, an important additionalmethod of use. Specifically, the level of sympathetic nerve activityseen in the perivascular space may be indicative of whether thepatient's hypertension is sympathetically driven. This would allow theclinician to decide whether denervation should be performed as well asproviding a baseline against which the post-denervation nerve activitycan be compared. It could also facilitate the choice of denervate vs.medicate and if medication is to be chosen, which medication would bebest for non-sympathetically driven hypertension.

Various other modifications, adaptations, and alternative designs are ofcourse possible in light of the above teachings. Therefore, it should beunderstood at this time that within the scope of the appended claims theinvention may be practiced otherwise than as specifically describedherein. It is contemplated that various combinations or subcombinationsof the specific features and aspects of the embodiments disclosed abovemay be made and still fall within one or more of the inventions.Further, the disclosure herein of any particular feature, aspect,method, property, characteristic, quality, attribute, element, or thelike in connection with an embodiment can be used in all otherembodiments set forth herein. Accordingly, it should be understood thatvarious features and aspects of the disclosed embodiments can becombined with or substituted for one another in order to form varyingmodes of the disclosed inventions. Thus, it is intended that the scopeof the present inventions herein disclosed should not be limited by theparticular disclosed embodiments described above. Moreover, while theinvention is susceptible to various modifications, and alternativeforms, specific examples thereof have been shown in the drawings and areherein described in detail. It should be understood, however, that theinvention is not to be limited to the particular forms or methodsdisclosed, but to the contrary, the invention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the various embodiments described and the appended claims.Any methods disclosed herein need not be performed in the order recited.The methods disclosed herein include certain actions taken by apractitioner; however, they can also include any third-party instructionof those actions, either expressly or by implication. For example,actions such as “sensing nerve activity using a catheter” include“instructing the sensing of nerve activity using a catheter.” The rangesdisclosed herein also encompass any and all overlap, sub-ranges, andcombinations thereof. Language such as “up to,” “at least,” “greaterthan,” “less than,” “between,” and the like includes the number recited.Numbers preceded by a term such as “approximately”, “about”, and“substantially” as used herein include the recited numbers (e.g., about10%=10%), and also represent an amount close to the stated amount thatstill performs a desired function or achieves a desired result. Forexample, the terms “approximately”, “about”, and “substantially” mayrefer to an amount that is within less than 10% of, within less than 5%of, within less than 1% of, within less than 0.1% of, and within lessthan 0.01% of the stated amount.

What is claimed is:
 1. A method of treating hypertension, comprising:positioning a distal portion of a catheter within a renal artery of ahuman patient; advancing a first needle guiding element and a secondneedle guiding element outward from the catheter toward an insidesurface of the renal artery; advancing a first needle and a secondneedle through the first needle guiding element and second needleguiding element, respectively, and into a peri-vascular space outside ofthe inside surface of the renal artery, wherein a distal end of thefirst needle guiding element and a distal end of the second needleguiding element are configured to maintain their position against theinside surface of the renal artery as the first needle and the secondneedle advance into the peri-vascular space; and operating the catheterto provide at least one modality of neurolysis to sympathetic nerveslocated in the peri-vascular space; and sensing nerve activity from atleast one of the first and second needles from locations outside of therenal artery.
 2. The method of treating hypertension as in claim 1,wherein the at least one modality of neurolysis includes injecting anablative fluid through the first needle and the second needle to formtwo ablative fluid zones in the peri-vascular space.
 3. The method ofclaim 2, wherein the ablative fluid injected from each needle into theperi-vascular space travels circumferentially forming one zone for eachneedle where the zones approximately intersect to form a ring ofneurolysis.
 4. The method of treating hypertension as in claim 2,wherein injecting the ablative fluid comprises injecting ethanol.
 5. Themethod of treating hypertension as in claim 1, wherein the at least onemodality of neurolysis includes providing ablation of sympathetic nervesusing energy delivered by at least the first needle, and operatingelectronic external circuitry in electrical communication to the firstneedle to provide the ablation.
 6. The method of treating hypertensionas in claim 5, where the energy delivered is in the radiofrequencyspectrum.
 7. The method of treating hypertension as in claim 5, wherethe energy delivered includes providing ultrasonic ablation from anultrasound transducer within a portion of the catheter, and operatingelectronic external circuitry in electrical communication to theultrasonic transducer.
 8. The method of treating hypertension as inclaim 1, further including evaluating the sensed nerve activity bycomparison to a treatment criterion.
 9. The method of treatinghypertension as in claim 5, wherein sensing nerve activity from thefirst needle uses a return that is provided by at least one of: thesecond needle, an electrode on the skin of the patient, or an electrodelocated on a body of a distal tip of the catheter.
 10. The method oftreating hypertension as in claim 1, wherein sensing nerve activityentails sensing nerve activity during two or more periods of timeseparated by at least 30 seconds.
 11. The method of claim 10, where thetwo or more periods of time include a first period of time beforeablation of the sympathetic nerves and a second period of time occurringafter ablation.
 12. The method of claim 11, further including evaluatingthe quality of neurolysis by calculating a comparison result between thesensed nerve activity after ablation to the sensed nerve activity beforeablation, and comparing this result to a treatment criterion.
 13. Themethod of treating hypertension as in claim 1, wherein the catheterincludes a third needle, and nerve activity is sensed between at leasttwo of the following needles: the first needle and the second needle,the first needle and the third needle, and the second needle and thethird needle.
 14. The method of treating hypertension as in claim 13,including evaluating the quality of neurolysis by comparison of thesensed nerve activity to a pre-set criterion.
 15. The method of treatinghypertension as in claim 14, further including sensing nerve activitybetween at least two of the following needles: the first needle and thesecond needle, the first needle and the third needle, and the secondneedle and the third needle.
 16. The method of treating hypertension asin claim 1, further including using external equipment to evaluate ameasurement of sensed nerve activity.
 17. The method of treatinghypertension as in claim 16, further including operating the catheter toprovide at least one modality of neurolysis to the sympathetic nerveslocated in the peri-vascular space based on the measurement of sensednerve activity.
 18. The method of treating hypertension as in claim 16,wherein using external equipment to evaluate the measurement of sensednerve activity includes providing a visual display of the sensed nerveactivity on a display.
 19. The method of treating hypertension as inclaim 16, wherein the measurement of sensed nerve activity includesmeasurement of one or more of: spike count, mean burst frequency, peakburst frequency, power within at least one spectral band, and anormalized measure of nerve activity which compares sensed nerveactivity after injection to sensed nerve activity before injection. 20.The method of treating hypertension as in claim 17, including haltingtherapy in the case where evaluation of sensed nerve activity does meeta treatment criterion after a pre-set number of repetitions of operatingthe catheter to provide at least one modality of neurolysis to thesympathetic nerves located in the peri-vascular space based on themeasurement of sensed nerve activity.
 21. The method of treatinghypertension as in claim 16, wherein evaluating the sensed activity inorder to assess whether the ablation procedure has provided sufficienttreatment, includes evaluation of sensed activity that includesproviding an auditory signal related to a measurement of the sensednerve activity on a speaker.
 22. A method of treating hypertension,comprising: positioning a distal portion of a catheter within a renalartery of a human patient; advancing at least a first needle guidingelement and a second needle guiding element outward from the cathetertoward an interior wall of the renal artery; advancing at least a firstneedle and a second needle through the first guiding element and thesecond needle guiding element and into a peri-vascular region outside ofthe interior wall of the renal artery, wherein a distal end of the firstneedle guiding element and a distal end of the second needle guidingelement are configured to maintain their position against the interiorwall of the renal artery as the first needle and the second needleadvance into the peri-vascular region; operating the catheter to provideat least a first modality of neurolysis to sympathetic nerves located ina peri-vascular space of the patient; and wherein the catheter isconfigured to sense nerve activity from at least one location in theperi-vascular region outside of the interior wall of the renal artery.23. The method of treating hypertension as in claim 22, furtherincluding using external equipment to provide a measurement of sensednerve activity.
 24. The method of claim 23, wherein the measurement ofsensed nerve activity is used to determine the efficacy of the firstmodality of neurolysis.
 25. The method of claim 24, wherein at leastpart of the method is repeated if the level of neurolysis isinsufficient.
 26. The method of claim 25, where a second modality ofneurolysis is applied, wherein the second modality of neurolysis isdifferent from the first modality of neurolysis.
 27. The method oftreating hypertension as in claim 23, wherein a visual display is usedto provide the measurement of the sensed nerve activity.
 28. The methodof treating hypertension as in claim 23, wherein the measurement ofsensed nerve activity includes measurement of one or more of: spikecount, mean burst frequency, peak burst frequency, power within at leastone spectral band, and a normalized measure of nerve activity whichcompares sensed nerve activity after injection to sensed nerve activitybefore injection.